Issa J. Dahabreh

Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer

BACKGROUND Somatic mutations of the k-RAS oncogene have been assessed as a mechanism of de-novo resistance to epidermal growth factor receptor (EGFR) tyrosine-kinase inhibition in patients with non-small-cell lung cancer (NSCLC), and to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer (mCRC). The aim of this systematic review and meta-analysis was to assess if k-RAS mutations represent a candidate predictive biomarker for anti-EGFR-targeted therapeutic strategies in mCRC and NSCLC. METHODS We systematically identified articles pertaining to k-RAS mutational status in patients with NSCLC treated with tyrosine-kinase inhibitors (TKI), and patients with mCRC treated with any anti-EGFR-based regimens. Eligible studies had to report complete responses (CR) and partial responses (PR), stratified by k-RAS mutational status. Potential between-study heterogeneity was accommodated by use of random-effects models for bivariable meta-analysis of sensitivity and specificity (the primary endpoints). The positive and negative likelihood ratios (+LR and -LR, respectively) of k-RAS mutations for predicting an absence of response were considered as secondary endpoints and were calculated by use of pooled estimates for sensitivity and specificity. FINDINGS Of 252 retrieved manuscripts, 17 were deemed eligible for the NSCLC meta-analysis (165 of 1008 patients with mutated k-RAS). The presence of k-RAS mutations was significantly associated with an absence of response to TKIs (sensitivity=0.21 [95% CI 0.16-0.28], specificity=0.94 [0.89-0.97]; +LR=3.52; -LR=0.84). Of 68 retrieved manuscripts reporting on anti-EGFR monoclonal-antibody-based treatment of mCRC, eight studies were deemed eligible for the final analysis (306 of 817 patients with mutated k-RAS). The presence of k-RAS mutations was significantly associated with an absence of response to anti-EGFR monoclonal-antibody-based treatments (sensitivity=0.47 [0.43-0.52]; specificity=0.93 [0.83-0.97]; +LR=6.82; -LR=0.57). INTERPRETATION This analysis provides empirical evidence that k-RAS mutations are highly specific negative predictors of response (de-novo resistance) to single-agent EGFR TKIs in advanced NSCLC; and similarly to anti-EGFR monoclonal antibodies alone or in combination with chemotherapy in patients with mCRC. The low sensitivity and relatively high -LR of k-RAS mutations for determining non-responsiveness clearly shows that additional mechanisms of resistance to EGFR inhibitors exist.

Trastuzumab in the Adjuvant Treatment of Early-Stage Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

BACKGROUND We performed a systematic review and meta-analysis to compare treatment outcomes for human epidermal growth factor receptor (HER)-2-positive breast cancer patients receiving adjuvant chemotherapy with or without trastuzumab. METHODS We identified randomized clinical trials comparing adjuvant chemotherapy with or without trastuzumab in patients with resectable breast cancer. Fixed-effects meta-analysis was used to combine data. RESULTS Five eligible trials were identified, reporting outcomes on 13,493 women. Fixed-effects analysis showed disease-free survival to be superior for trastuzumab-treated patients (risk ratio [RR], 0.62; 95% confidence interval [CI], 0.56-0.68). Superiority was also observed for patients receiving trastuzumab with respect to mortality (RR, 0.66; 95% CI, 0.57-0.77), locoregional recurrence (RR, 0.58; 95% CI, 0.43-0.77), and distant recurrence (RR, 0.60; 95% CI, 0.52-0.68). Patients receiving trastuzumab with chemotherapy had a higher risk for congestive heart failure (RR, 7.60; 95% CI, 4.07-14.18) and left ventricular ejection fraction decline (RR, 2.09; 95% CI, 1.84-2.37). A higher risk for central nervous system metastasis as the first recurrence event (RR, 1.60; 95% CI, 1.06-2.40) was also noted in patients receiving trastuzumab. CONCLUSIONS The use of trastuzumab should be considered an integral part of the adjuvant therapy of HER-2-positive breast cancer patients.

Somatic EGFR mutations and efficacy of tyrosine kinase inhibitors in NSCLC

Early clinical studies of tyrosine kinase inhibitors (TKIs) that target the EGFR in patients with advanced non-small-cell lung cancer (NSCLC) showed that some patients experienced rapid, durable, complete or partial responses. These data were the basis for attempts to identify specific subgroups of patients who would further benefit from these agents. The discovery of somatic mutations in EGFR that correlated with sensitivity to TKIs identified a plausible explanation for these observations. Clinical and pathological factors such as female sex, never having smoked, Asian origin and adenocarcinoma histology correlate with the presence of EGFR mutations and objective responses to TKIs in patients with NSCLC. Recent studies in metastatic colorectal cancer highlighted that somatic mutations in KRAS represent a negative predictor of response to anti-EGFR monoclonal antibodies; KRAS mutations also represent an important mechanism of resistance to TKIs in NSCLC. Many large clinical studies are currently investigating the predictive and prognostic value of EGFR mutational status and other candidate biomarkers. We summarize the literature and present an overview of the field of anti-EGFR therapy in NSCLC, focusing on the influence of somatic EGFR mutations on selection of patients for TKI therapy and the influence of EGFR pathway regulation.

Index Event Bias as an Explanation for the Paradoxes of Recurrence Risk Research

A review of the recurrence risk literature uncovers several paradoxical observations: thrombolphilias predispose for a first episode of deep venous thrombosis (DVT) but not for recurrence (the thrombophilia paradox1); aspirin takers are at lower risk for cardiac events, but higher risk of recurrence (the aspirin paradox2); and while obesity is an established risk factor for coronary artery disease, it appears to protect against recurrent coronary events (the obesity paradox3). While several hypotheses have been proposed to explain these paradoxes, it is not generally appreciated that all recurrent risk analyses are prone to a particular bias that may induce such paradoxical results. We call it “index event bias” because it arises in studies that select patients based on the occurrence of an index event. We demonstrate how “index event bias” emerges and that – because of the general congruence between risk factors for the index and recurrent events – it will generally tend to bias studies toward the null, causing their contribution to be substantially underestimated or even reversed. We use the association between patent foramen ovale (PFO) and cryptogenic stroke as a prototypical example, and describe several other instances where it may have affected study results. PFO and the risk of stroke Although the prevalence of PFO in the general population is 25%, it is approximately double among cryptogenic stroke patients.4 This association is attributed to paradoxical embolism, i.e. a thromboembolus from the venous system gaining access to the arterial circulation via a right-to-left shunt in the heart. The consistent association of PFO with cryptogenic stroke (suggesting a pathogenic role for this otherwise benign congenital anomaly) has been accompanied by a surprising yet equally consistent finding: PFO is not a risk factor for recurrent stroke.4 The discrepancy can be reconciled by the following observation: among patients with a cryptogenic stroke, those with a PFO tend to be younger, have approximately half the rate of diabetes and hypertension and are less likely to have hypercholesterolemia or smoke.4 Thus, the similarity in recurrence rates in patients with cryptogenic stroke with or without PFO suggests that PFO is an important risk factor for stroke recurrence, since it “compensates” for a profound shortfall in conventional stroke risk factors. Index event bias When multiple risk factors contribute to the risk of an outcome, conditioning on the outcome induces dependence between the risk factors, even when they are independently distributed in the general population (e.g. there is no association between PFO and diabetes, hypertension, hypercholesterolemia in the general population, but there is a negative association in the cryptogenic stroke population). Heuristically, the association may be thought to arise because patients with PFOs do not require the same burden of stroke risk factors to have the index event; thus the presence of a PFO “protects” cryptogenic stroke patients from other risk factors (both known and unknown), see Table.5-6 Because risk factors often have congruent effects on the index and recurrent events, this negative association will tend to bias any estimation of the PFO effect on recurrence risk towards the null, unless there is a thorough accounting for all shared risk factors7 (for example, in a recent study propensity score matched analysis eliminated the obesity paradox8). Obviously, bias will always be a concern since unknown risk factors are often operating to cause a disease. More generally, the biases we describe are special cases of “collider bias”, which is well described in the epidemiologic literature.9 Table Distribution of selected established stroke risk factors in “unselected” individuals and individuals who have had an index stroke event, stratified by PFO status. It is apparent that conditioning on the index stroke radically changes the ... A threat for causal inference in recurrence risk research “Index event bias” is often underappreciated and should be considered as a possible contributing factor to many of the paradoxes enumerated in the introduction. As with PFO, thrombophilias presumably contribute to the risk of a second DVT, but they also “protect” against other DVT risk factors among patients with a first event. Similarly, not taking aspirin will “protect” against other heart attack risk factors among patients with a first heart attack. While the assumptions required to be mathematically certain that one risk factor will consistently “protect” against the presence of others are very stringent and not typically met in the real world,7 dependence between risk factors will occur in all studies that select participants based on the occurrence of a first event because the selection influences the distribution of risk factors in the patients that are included in the study and affects the association of these risk factors with the outcome of interest (the recurrent event).9 However, in such cases, the distribution of the risk factors and the behavior of the bias in estimating causal effects are unpredictable. In addition to being a ubiquitous issue with studies examining risk factors of recurrence, index event bias may affect research that examines disease progression and severity, when there are multiple risk factors for progression or for severity that are also risk factors for having the disease in the first place. For example, the so-called “smokers paradox” describes the better prognosis of smokers compared to non-smokers among patients with myocardial infarction.10 Also, among patients with heart failure, better survival has been associated not only with obesity, but with higher blood pressure and higher levels of low-density lipoprotein and higher total cholesterol – both established risk factors for the development of heart failure. Readers should keep in mind that the true causal models underlying the associations discussed in this commentary are unknown. For many of the above examples, other factors no doubt also contribute. Presumably “confounding by indication” also plays a role in the emergence of the aspirin paradox (since those with more risk factors may have preferentially been prescribed aspirin) and some of the “reverse epidemiology” seen in the context of heart failure and other diseases may actually reflect unknown causal pathways. Our purpose is to underscore how the tenuous relationship between association and causation becomes even more so in the context of recurrence risk research employing simple regression models. In this context – because the index and recurrent events have common risk factors – many so-called paradoxes should actually be expected, since they are induced by conditioning the analyses on the occurrence of the index event.

Hematologic manifestations and predictors of lymphoma development in primary Sjögren syndrome: clinical and pathophysiologic aspects.

The diverse hematologic manifestations of primary Sjögren syndrome (pSS) have not been systematically investigated, and their prognostic relevance remains unclear. We conducted a retrospective study of 536 consecutive patients followed in our institution to assess the prevalence of hematologic abnormalities and their associations with various disease manifestations in pSS. We also aimed to identify risk factors for the development of non-Hodgkin lymphoma (NHL) overall and by subtype. Anemia of chronic disease and hypergammaglobulinemia were the most prevalent hematologic manifestations encountered at diagnosis and during the course of pSS. Univariate analysis between cytopenias and glandular manifestations revealed a statistically significant correlation between lymphocytopenia and parotid gland enlargement (p = 0.002), as well as between neutropenia and xerostomia (p = 0.019). Anemia, lymphocytopenia, thrombocytopenia, hypergammaglobulinemia, the presence of monoclonal serum proteins, and cryoglobulinemia correlated significantly with the presence of extraglandular symptoms such as palpable purpura, lymphadenopathy, and splenomegaly. Lymphoma was diagnosed in 7.5% (95% confidence interval [CI], 5.4%-10%) of patients. Marginal zone B-cell lymphomas (MZBCLs) were the predominant histologic type (65%; 95% CI, 48.3%-79.4%), while diffuse large B-cell lymphomas (DLBCLs) accounted for 17.5% (95% CI, 7.3%-32.8%) of all cases. The development of NHL in patients with pSS could be predicted by the presence of simple clinical and laboratory factors at diagnosis: neutropenia (p = 0.041), cryoglobulinemia (p = 0.008), splenomegaly (p = 0.006), lymphadenopathy (p = 0.021), and low C4 levels (p = 0.009). Patients carrying any of these factors had a more than 5-fold increased risk of NHL compared to patients with no risk factors at all. The above set of disease characteristics could predict subsequent development of MZBCL; the presence of lymphocytopenia (p = 0.044) at diagnosis served as a risk factor for the development of a non-MZBCL, most commonly DLBCL. Anemia of chronic disease and hypergammaglobulinemia are common hematologic manifestations at diagnosis and during the course of pSS. Neutropenia and cryoglobulinemia at diagnosis are significantly associated with an increased risk of lymphoma development. Abbreviations: AECC = American-European Consensus Classification, CI = confidence interval, DLBCL= diffuse large B-cell lymphoma, HR = hazard ratio, MALT = mucosa-associated lymphoid tissue, MZBCL = marginal zone B-cell lymphoma, NHL = non-Hodgkin lymphoma, NPV = negative predictive value, PPV = positive predictive value, pSS = primary Sjögren syndrome.

Systematic Review: Anti-Epidermal Growth Factor Receptor Treatment Effect Modification by KRAS Mutations in Advanced Colorectal Cancer

BACKGROUND KRAS mutations have been extensively investigated as predictive biomarkers for treatment of advanced colorectal cancer with the anti-epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab. PURPOSE To summarize whether KRAS mutation status modifies effects of anti-EGFR-based treatments for patients with advanced colorectal cancer and whether KRAS status predicts clinical outcomes among such patients. DATA SOURCES MEDLINE and 2 curated genetics databases (through 24 March 2010) were searched for observational studies. MEDLINE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effects (through 1 September 2010) were searched for randomized, controlled trials. No search was restricted by language. STUDY SELECTION Three reviewers screened titles and abstracts to identify published studies assessing KRAS mutations as predictors of overall and progression-free survival or treatment failure for patients who received anti-EGFR-based therapy for metastatic colorectal cancer. DATA EXTRACTION Three investigators extracted data on population and study-design characteristics, including quality items, and on outcomes of interest. Random-effects meta-analyses were done on nonoverlapping studies. DATA SYNTHESIS In 4 reanalyses of randomized trials of anti-EGFR-based therapy versus best supportive care or cytotoxic chemotherapy, no significant benefit was found for overall or progression-free survival from anti-EGFR-based treatment among KRAS-positive patients (hazard ratio [HR], 1.0). However, evidence favors anti-EGFR therapy among KRAS wild-type patients; the relative HR across KRAS-positive and wild-type patients was 1.30 (95% CI, 0.95 to 1.78) for overall survival and 2.22 (CI, 1.74 to 2.84) for progression-free survival by random-effects meta-analysis. In 13 cohorts of patients who received anti-EGFR antibodies, the summary HR for overall survival was 1.79 (CI, 1.48 to 2.17), with better survival in wild-type patients. The corresponding HR for progression-free survival was 2.11 (CI, 1.74 to 2.55 [16 cohorts]). In random-effects bivariate meta-analysis of 22 studies, the summary sensitivity of KRAS mutations for predicting lack of response was 0.49 (CI, 0.43 to 0.55), and summary specificity was 0.93 (CI, 0.87 to 0.97). LIMITATIONS Limited evidence from randomized studies exists. Patient-level data are needed to assess modifiers of the mutation-by-treatment interaction. Publication bias could be a concern. CONCLUSION KRAS mutations are consistently associated with reduced overall and progression-free survival and increased treatment failure rates among patients with advanced colorectal cancer treated with anti-EGFR antibodies. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Somatic EGFR Mutation and Gene Copy Gain as Predictive Biomarkers for Response to Tyrosine Kinase Inhibitors in Non–Small Cell Lung Cancer

Purpose: The aim of this systematic review and meta-analysis was to characterize common EGFR molecular aberrations as potential predictive biomarkers for response to monotherapy with tyrosine kinase inhibitors (TKI) in non–small cell lung cancer (NSCLC). Experimental Design: We systematically identified articles investigating EGFR status [somatic mutational and gene copy aberrations (copy number)] in patients with NSCLC treated with TKIs. Eligible studies had to report complete and partial response rates stratified by EGFR status. We used random effects models for bivariable meta-analysis of sensitivity and specificity; positive and negative likelihood ratios (+LR and −LR, respectively) were also calculated and were considered as secondary end points. Results: Among 222 retrieved articles, 59 were considered eligible for the somatic EGFR mutation meta-analysis (1,020 mutations among 3,101 patients) and 21 were considered eligible for the EGFR gene copy number meta-analysis (542 gene gain among 1,539 patients). EGFR mutations were predictive of response to single-agent TKIs [sensitivity, 0.78; 95% confidence interval (95% CI), 0.74-0.82; specificity, 0.86; 95% CI, 0.82-0.89; +LR, 5.6; −LR, 0.25]. EGFR gene gain was also associated with response to TKIs, albeit with lower sensitivity and specificity. In subgroup analysis, the only recognized trend was for a higher predictive value in Whites compared with East Asians for both mutation and gene copy number. Conclusion: This analysis provides empirical evidence that EGFR mutations are sensitive and specific predictors of response to single-agent epidermal growth factor receptor TKIs in advanced NSCLC. The diagnostic performance of mutations seems better than that of EGFR gene gain. Clin Cancer Res; 16(1); 291–303

Association of Episodic Physical and Sexual Activity With Triggering of Acute Cardiac Events: Systematic Review and Meta-analysis

CONTEXT Evidence has suggested that physical and sexual activity might be triggers of acute cardiac events. OBJECTIVE To assess the effect of episodic physical and sexual activity on acute cardiac events using data from case-crossover studies. DATA SOURCES MEDLINE and EMBASE (through February 2, 2011) and Web of Science (through October 6, 2010). STUDY SELECTION Case-crossover studies investigating the association between episodic physical or sexual activity and myocardial infarction (MI) or sudden cardiac death (SCD). DATA EXTRACTION Two reviewers extracted descriptive and quantitative information from each study. We calculated summary relative risks (RRs) using random-effects meta-analysis and absolute event rates based on US data for the incidence of MI and SCD. We used the Fisher P value synthesis method to test whether habitual physical activity levels modify the triggering effect and meta-regression to quantify the interaction between habitual levels of physical activity and the triggering effect. RESULTS We identified 10 studies investigating episodic physical activity, 3 studies investigating sexual activity, and 1 study investigating both exposures. The outcomes of interest were MI (10 studies), acute coronary syndrome (1 study), and SCD (3 studies). Episodic physical and sexual activity were associated with an increase in the risk of MI (RR = 3.45; 95% confidence interval [CI], 2.33-5.13, and RR = 2.70; 95% CI, 1.48-4.91, respectively). Episodic physical activity was associated with SCD (RR = 4.98; 95% CI, 1.47-16.91). The effect of triggers on the absolute rate of events was limited because exposure to physical and sexual activity is infrequent and their effect is transient; the absolute risk increase associated with 1 hour of additional physical or sexual activity per week was estimated as 2 to 3 per 10,000 person-years for MI and 1 per 10,000 person-years for SCD. Habitual activity levels significantly affected the association of episodic physical activity and MI (P < .001), episodic physical activity and SCD (P < .001), and sexual activity and MI (P = .04); in all cases, individuals with lower habitual activity levels had an increased RR for the triggering effect. For every additional time per week an individual was habitually exposed to physical activity, the RR for MI decreased by approximately 45%, and the RR for SCD decreased by 30%. CONCLUSION Acute cardiac events were significantly associated with episodic physical and sexual activity; this association was attenuated among persons with high levels of habitual physical activity.

Patent Foramen Ovale Closure and Medical Treatments for Secondary Stroke Prevention A Systematic Review of Observational and Randomized Evidence

Background and Purpose— Patients discovered to have a patent foramen ovale in the setting of a cryptogenic stroke may be treated with percutaneous closure, antiplatelet therapy, or anticoagulants. A recent randomized trial (CLOSURE I) did not detect any benefit of closure over medical treatment alone; the optimal medical therapy is also unknown. We synthesized the available evidence on secondary stroke prevention in patients with patent foramen ovale and cryptogenic stroke. Methods— A MEDLINE search was performed for finding longitudinal studies investigating medical treatment or closure, meta-analysis of incidence rates (IR), and IR ratios of recurrent cerebrovascular events. Results— Fifty-two single-arm studies and 7 comparative nonrandomized studies and the CLOSURE I trial were reviewed. The summary IR of recurrent stroke was 0.36 events (95% confidence interval [CI], 0.24–0.56) per 100 person-years with closure versus 2.53 events (95% CI, 1.91–3.35) per 100 person-years with medical therapy. In comparative observational studies, closure was superior to medical therapy (IR ratio=0.19; 95% CI, 0.07–0.54). The IR for the closure arm of the CLOSURE I trial was higher than the summary estimate from observational studies; there was no significant benefit of closure over medical treatment (P=0.002 comparing efficacy estimates between observational studies and the trial). Observational and randomized data (9 studies) comparing medical therapies were consistent and suggested that anticoagulants are superior to antiplatelets for preventing stroke recurrence (IR ratio=0.42; 95% CI, 0.18–0.98). Conclusions— Although further randomized trial data are needed to precisely determine the effects of closure on stroke recurrence, the results of CLOSURE I challenge the credibility of a substantial body of observational evidence strongly favoring mechanical closure over medical therapy.

Is JAK2 V617F mutation more than a diagnostic index? A meta-analysis of clinical outcomes in essential thrombocythemia.

A systematic review and meta-analysis was carried out to compare the frequency of clinically significant outcomes between JAK2 V617F positive and wild type patients with essential thrombocythemia (ET). JAK2 V617F positivity in patients with ET was associated with a clear increase in the odds of thrombosis [OR=1.83 (95% CI, 1.32-2.53), p<0.0001], and much higher odds of transformation to polycythemia vera [OR=7.67 (95% CI, 2.04-28.87), p=0.0009]. The mean difference of the white blood cell count between JAK2 positive and negative patients was associated with an increased odds ratio for thrombosis (p=0.02). The JAK2 V617F mutation in patients with ET is associated with an increased risk of adverse cardiovascular outcomes via an increase in the leukocyte count.