Serum neuregulin 1 in relation to ventricular function and subclinical atherosclerosis in type 2 diabetes patients.

BACKGROUND AND AIMS: Neuregulin 1 (NRG-1) is one of the members of the epidermal growth factors proteins. The present study provides novel insights into the relationship between serum levels of NRG-1 and insulin resistance, subclinical atherosclerosis and cardiac dysfunction that occur in type 2 diabetes (T2D). METHODS: The study included 50 patients with T2D and 40 healthy age- and gender-matched controls. Serum NRG-1 was measured using ELISA. Glycemic parameters, lipid profile and insulin resistance were assessed. Trans-thoracic echocardiography and carotid intima media thickness (CIMT) were studied for all study subjects. RESULTS: T2D patients had significantly lower serum NRG-1 levels than controls. Serum NRG-1 was negatively correlated with age, fasting blood glucose, HbA1c, insulin resistance, blood urea, serum creatinine and LDL-C, and positively correlated with HDL-C, eGFR and CIMT. Regarding echocardiographic variables, serum NRG-1 was found to correlate positively with left ventricular global longitudinal strain and negatively with E/Ea ratio. NRG-1 was found to predict subclinical atherosclerosis in type 2 diabetes patients at a cut-off value<108.5pg/ml with 78% sensitivity and 80% specificity. CONCLUSIONS: A robust relationship was found between serum NRG-1 levels and hyperglycemia, insulin resistance, subclinical atherosclerosis, and cardiac dysfunction in patients with type 2 diabetes. These results shed light on a possible role of NRG-1 as a potential noninvasive biomarker for detection of cardiometabolic risk in T2D.

METFORMIN EFFECTS ON NEUREGULIN-1 IN POLYCYSTIC OVARIAN WOMEN.

The study aims to assess the levels of Neuregulin 1 (NRG1) in patients with Polycystic Ovary Syndrome (PCOS) and to determine the impact of metformin treatment on their serum NRG1 levels. PCOS is a common endocrine disorder in women of reproductive age, while NRG1 is linked to regulating inflammation and ovulation. The study was conducted on sixty women with PCOS and thirty healthy women as the control group. Thirty patients completed the follow-up study and continued on metformin treatment for three months. The study was a cross-sectional study done in Salah Al-Deen general hospital/gynaecology and obstetrics department in Tikrit City from November 2022 to January 2023. The participants were diagnosed with PCOs based on the Rotterdam criteria, and their BMI and insulin resistance were measured before and after therapy. Fasting serum NRG1 was also measured. The study found that women with PCOS had increased levels of fasting blood glucose, insulin, and insulin resistance, as well as increased levels of NRG1. However, treatment with metformin for three months resulted in a significant decrease in body mass index, blood glucose, insulin, and insulin resistance. NRG1 level decreased significantly after 3 months of treatment with 850 mg per day with metformin in women with PCOS.

The importance of circulating levels of salusin-α, salusin-ß, and heregulin-ß1 in atherosclerotic coronary arterial disease.

OBJECTIVE: The relationship between the severity of atherosclerotic coronary artery disease (CAD) and circulating levels of salusin-α, salusin-ß and heregulin-ß1 has been investigated. In addition, the relationship with these peptides and high sensitive C-reactive protein (hsCRP) has been investigated. METHODS: The study was conducted on 55 volunteers who had normal coronary angiography (CAG) as the control group, 35 volunteers with the degree of coronary artery stenosis below 50% in CA as the non-critical stenosis group, 37 volunteers with narrowing of one coronary artery above 50% as single vessel group and 41 volunteers with narrowing of more than one coronary artery above 50% as multi-vessel group. One hundred and thirteen volunteers have been included to CAD group. RESULTS: There was no statistically significant difference in serum salusin-α levels between groups. Serum salusin-ß ve hsCRP levels were significantly lower in control group compared to other groups and CAD group. There was no statistically significant difference in salusin-ß and salusin-α levels in reciprocal comparison of other groups other than heregulin-ß1 levels. Heregulin-ß1 levels were significantly lower in 'non-critical occlusion' and 'multiple artery occlusion' groups compared to control group. Heregulin-ß1 levels in 'single artery occlusion' group were significantly higher than control, 'non-critical occlusion' and 'multiple artery occlusion' groups. CONCLUSION: Salusin-α levels does not indicate any significant differences between any groups in our study however the relationship of salusin-α with salusin- ß and heregulin-ß1 levels drives to cogitate that these peptides can be used as biomarkers and therapeutic approaches in CAD. We think that these peptides will be used in laboratories routinely in future in addition to hsCRP for CAD.

Increased Levels of Serum Neuregulin 1 Associated with Cognitive Impairment in Vascular Dementia.

OBJECTIVE: Neuregulin 1 (NRG 1) is a member of the epidermal growth factor (EGF) family and is believed to play an important role in neuroplasticity. However, the relationship between NRG 1 and vascular dementia (VaD) is poorly understood. The purpose of this study is to explore the correlation between neuregulin 1 and VaD. Patients and Methods. From October 2018 to September 2020, 93 VaD patients and 79 control populations who attended Liaocheng People's Hospital were included in the study. Baseline characteristics including age, gender, years of education, HDL, LDL, FBG, SBP, and DBP are collected. At the same time, peripheral blood was collected, and the concentration of serum NRG 1 was detected by enzyme-linked immunosorbent assay (ELISA). All research subjects received professional cognitive function assessment. RESULTS: A total of 93 VaD patients and 79 controls were enrolled. There was no significant difference in age, gender, years of education, HDL, LDL, FBG, SBP, and DBP between the two groups (p > 0.05). However, compared with the control group, VaD patients have lower MoCA and higher serum NRG 1 levels, and the difference is statistically significant (p < 0.001). The correlation analysis of MoCA and baseline characteristics showed that the MoCA score in VaD was significantly negatively correlated with serum NRG 1 (r = -0.374, p = 0.036). The results of multivariate regression showed that the MoCA score of VaD patients was only associated with NRG 1 (ß = 0.258, p = 0.012). CONCLUSIONS: The concentration of serum NRG 1 in VaD patients is significantly increased, which may be an independent risk factor for cognitive impairment in VaD patients.

Sex differences in circulating neuregulin1-ß1 and ß-secretase 1 expression in childhood-onset schizophrenia.

OBJECTIVE: Early-onset schizophrenia is a severe and rare form of schizophrenia that is clinically and neurobiologically continuous with the adult form of schizophrenia. Neuregulin1 (NRG1)-mediated signaling is crucial for early neurodevelopment, which exerts its function by limited ß-secretase 1 (BACE1) proteolysis processing. However, circulating neuregulin1-ß1 (NRG1-ß1), an isoform of NRG1, and its cleavage enzyme BACE1 have not been studied in early-onset patients with schizophrenia. METHODS: In this study, we collected plasma and clinical information from 71 young patients (7 ≤ age years ≤20) with schizophrenia and 53 age- and sex-matched healthy controls. Immunoassay was used to test levels of circulating NRG1-ß1 and BACE1 expression. We further analyzed the relationship of disease-onset age and gender with NRG1-ß1 and BACE1 levels. RESULTS: We found that circulating plasma levels of NRG1-ß1 were significantly decreased in young patients with early-onset schizophrenia. In males with childhood onset schizophrenia (COS), NRG1-ß1 was reduced and was inversely correlated with positive symptom of PANSS; moreover, these male patients with higher plasma BACE1 levels showed more severe general symptoms of PANSS and defective social functioning; whereas, no aforementioned results were found in adolescent-onset schizophrenia (AOS). Notably, young female patients with COS and AOS had no significant change in NRG1-ß1 and BACE1, which demonstrated a sex-dependent effect in early-onset schizophrenia. CONCLUSION: Our results suggest that decreased levels of NRG1-ß1 and its cleavage enzyme BACE1 contribute to increased risk of etiology of schizophrenia. Synthetic biomarkers may have clinical applications for the early diagnosis of male COS.

The Relationship Between Circulating Neuregulin-1 and Coronary Collateral Circulation in Patients with Coronary Artery Disease.

Coronary collateral circulation (CCC) plays a crucial role in myocardial blood supply, especially for ischemic myocardium. Previous study has shown that neuregulin-1 is a prominent angiogenic factor in diabetic cardiomyopathy, whereas the relationship between neuregulin-1 and CCC has not been investigated. Thus, we aimed to investigate relationship between circulating neuregulin-1 levels and CCC in stable coronary artery disease patients.Coronary artery disease patients with a stenosis of ≥ 90% as evidenced by coronary angiography were included in our study. According to the Rentrop-Cohen classification, coronary collateral degree was graded as 1 to 4. Patients with collateral degree grade 0 or 1 were enrolled in poor CCC group, whereas patients with grade 2 or 3 were enrolled in good CCC group.Plasma neuregulin-1 level was significantly increased in good collateral group and positively related to Rentrop grade (P < 0.01). Multivariate regression analysis and ROC (receiver operating characteristic curve) revealed that plasma neuregulin-1 could predict CCC status effectively.Increased plasma neuregulin-1 level was related to better CCC in patients with coronary artery disease. Neuregulin-1 was an independent and reliable predictor for good coronary collateral development and provided a potential therapeutic strategy to reduce myocardial ischemia injury.

Genetic variation in NRG 1 gene and risk of post-traumatic stress disorders in patients with hepatocellular carcinoma.

OBJECTIVE: Neuregulin 1 (NRG1) was proved to play an important role in numerous neurodevelopmental processes. In our study, we aimed to investigate the relationship between the NRG1 gene polymorphism and the cognitive function of patients with hepatocellular carcinoma (HCC) complicated with post-traumatic stress disorders (PTSD) before and after the psychological intervention. METHODS: Mini-mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Loewenstein Occupational Therapy Cognitive Assessment (LOTCA) were used for cognitive function assessment. Serum level of NRG1 was detected by ELISA, and the correlation between NRG1 level and cognitive function was analyzed. The difference of cognitive function score of patients with HCC complicated with PTSD before and after psychological intervention was compared, and the relationship between rs35753505 and rs3924999 polymorphism with the score was analyzed. RESULTS: Patients with HCC complicated with PTSD showed decreased serum NRG1 level. NRG1 levels of patients in the HCC + PTSD group were positively correlated with MMSE, MoCA, and LOTCA scores. In rs35753505, the CC genotype was a risk factor for the occurrence of PTSD in patients with HCC, while in rs3924999, the GG genotype was a risk factor for the occurrence of PTSD in patients with HCC. After psychological intervention, the CC genotype at rs35753505 and the GG genotype at rs3924999 were susceptible genotypes. CONCLUSION: CC genotype at rs35753505 and GG genotype at rs3924999 of NRG1 gene increased the risk of PTSD in patients with HCC. CC and GG genotypes were susceptible after psychological intervention.

Vitamin D and Neurotrophin Levels and Their Impact on the Symptoms of Schizophrenia.

INTRODUCTION: Vitamin D is involved in brain development and functioning, as well as in regulation of neurotrophic factors. Changes in the expression of those factors are possibly responsible for morphologic abnormalities and symptoms in patients suffering from schizophrenia. OBJECTIVE: The main goal of this research was to investigate the interrelationship between vitamin D, nerve growth factors (NGF, brain-derived neurotrophic factor [BDNF], and neuregulin-1 [NRG1]), and schizophrenia symptom domains. METHODS: This research included 97 inpatients diagnosed with schizophrenia. Schizophrenia symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Blood samples were taken in order to analyze concentrations of vitamin D, BDNF, NRG1, and NGF growth factors. The obtained results were used in a multiple regression analysis. RESULTS: The vitamin D concentration positively affected the concentration of NRG1 (F = 8.583, p = 0.005) but not the concentration of other investigated growth factors (BDNF and NGF). The clinical characteristics and symptom domains of schizophrenia seemed to be unaffected by the concentrations of vitamin D, BDNF, and NGF, while the NRG1 concentration significantly affected positive symptom domains of schizophrenia (F = 4.927, p = 0.030). CONCLUSION: The vitamin D concentration positively affected NRG1 levels but not schizophrenia symptomatology as measured by PANSS. The as-sociation between the two could be intermediated via NRG1.

The Level of Neuregulin-1 after Traumatic Brain Injury and Formation of Post-Traumatic Epilepsy.

We evaluated the serum level of neuregulin-1 in humans with traumatic brain injury. The highest levels of neuregulin-1 were revealed in patients with developing post-traumatic epilepsy and the lowest concentrations of this peptide were found in healthy controls. The patients with traumatic brain injury not aggravated by the development of post-traumatic epilepsy had intermediate levels of neuregulin-1.

Circulating neuregulin-1 levels in polycystic ovary syndrome.

Neuregulin-1 (NRG1) has been shown to be associated with the regulation of inflammation and ovulation. The aim of this study was to investigate the relationship between serum NRG1 levels and various clinical and metabolic parameters in women with polycystic ovary syndrome (PCOS). This case-controlled study included 38 women with PCOS and 46 age and body mass index (BMI)-matched controls without PCOS. The serum NRG1 levels of the women with PCOS were found to be significantly lower compared to the control group. The high sensitivity C-reactive protein (hs-CRP) levels of the PCOS subjects were significantly higher than in the control group. The circulating NRG1 levels were negatively correlated with a homeostasis model assessment of insulin resistance (HOMA-IR) and the hs-CRP in the PCOS group. There is no significant correlation between the circulating NRG1 levels and the serum insulin in the PCOS group. There was a trend toward high NRG1 levels in the PCOS subjects with high BMI, but the difference failed to reach a statistical significance. Decreased NRG1 levels in PCOS subjects may be associated with insulin resistance and a low-grade chronic inflammation. Impact statement What is already known on this subject? Although there have been many studies related to NRG1, we could not find any study explaining the relationship between NRG1 and PCOS. This study provides first and novel insights into the relationship between serum NRG1 levels and the insulin resistance in women with PCOS. What do the results of this study add? A decline in the NRG1 levels in PCOS may be associated with insulin resistance and a low-grade chronic inflammation. What are the implications of these findings for clinical practice and/or further research? Decreased NRG1 levels may play an important role in the reproductive and endocrine properties of PCOS. We think that NRG1 research may be contribute to the clarification of PCOS pathophysiology. Future research investigating NRG1 levels in obese and non-obese cases, as well as in ovulatory and anovulatory PCOS patients, will make a significant contribution to the resolution of the mystery under PCOS aetiology.

Elevated cleavage of neuregulin-1 by beta-secretase 1 in plasma of schizophrenia patients.

Neuregulin 1 (NRG1) is a key candidate susceptibility gene for schizophrenia. It is reported that the function of NRG1 can be regulated by cleavage via the ß-Secretase (BACE1), particularly during early development. While current knowledge suggested that schizophrenia might have different phenotypes, it is unknown whether BACE1-cleaved-NRG1 (BACE1-NRG1) activity is related to clinical phenotypes of schizophrenia. In the current study, we used a newly developed enzymatic assay to detect BACE1-NRG1 activity in the human plasma and investigated the levels of cleavage of NRG1 by BACE1 in the plasma from schizophrenia patients. Our results are the first to demonstrate that the level of plasma BACE1-NRG1 activity was significantly increased in subjects affected with schizophrenia compared with healthy controls. Interestingly, the elevated BACE1-NRG1 activity was correlated with the disease severity and duration of schizophrenia, such as patients suffering from shorter-term course and worse disease status expressed higher BACE1-NRG1 activity levels compared to whom with longer duration and less severity of the disease. Furthermore, this is also the first report that the alternation of BACE1-NRG1 activity was a substrate -specific event in schizophrenia. Together, our findings suggested that the plasma BACE1-NRG1 activity can be a potential biomarker for the early diagnosis of schizophrenia.

Neuregulin1 types mRNA level changes in autism spectrum disorder, and is associated with deficit in executive functions.

BACKGROUND: Autism spectrum disorder (ASD) is a pediatric heterogeneous psychiatric and neurodevelopmental disorder with social and communication deficits, language impairment and ritualistic or repetitive behaviors. ASD has significant genetic bases but candidate genes and molecular mechanisms of disorder are not clarified. Neuregulin1 (NRG1) gene, located in 8p12 is involved in development of central nervous system and was indicated as candidate gene in schizophrenia. METHODS: mRNA level of types I, II and III of NRG1 gene were studied in peripheral blood of 1540 ASD patients (IQ > 70) and 1490 control children by quantitative Real Time PCR. Also three domains of executive functions (working memory, response inhibition and vigilance) were examined in all subjects. FINDINGS: All three types were significantly down regulated in ASD patients. Significant deficiencies in executive functions (EF) were found in ASD patients. EF deficiencies mostly were associated with down expression of mRNA level of types I and III. Also correlations were found between NRG1 expression with gender and severity of ASD symptoms. INTERPRETATIONS: Findings primarily have been suggested involvement of NRG1 in etiology of ASD. Also correlation of NRG1 mRNA level with EF deficiencies could shed lights on EF mechanisms and may suggest targeted treatments to improve particular executive functions. FUND: Young researchers and elites club funded the project due to the annual grant of special talents of Club that gave to Arvin Haghighatfard.

Levels of peripheral Neuregulin 1 are increased in non-medicated autism spectrum disorder patients.

Though schizophrenia and autism spectrum disorders (ASD) are separate diseases, they have some common clinical manifestations and common pathogenic mechanisms. Numerous genes are associated with these conditions. Among these genes, Neuregulin-1 forms a risk for schizophrenia and some studies have shown polymorphism of this gene accompanies schizophrenia. NRG1 has a wide variety of functions, including neuronal migration, axon guidance, synaptic transmission, oligodendroglial maturation, and neurite outgrowth. To date, NRG1 levels have not been researched in ASD patients and considering the neurodevelopmental effects of NRG1, this study aimed to research the peripheral NRG1 levels in ASD patients. The study compared 32 ASD patients and 32 healthy controls. Serum NRG-1 levels were measured with ELISA. In ASD patients (mean ±â€¯SD, 10.80 ±â€¯4.78 ng/ml), the NRG1 levels were found to be statistically significantly high compared to the health control group (mean ±â€¯SD, 6.92 ±â€¯4.91 ng/ml) (p = 0.004). According to the results we obtained, NRG1 was shown to play a possible role in ASD pathogenesis. There is a need for advanced studies on the possible role of NRG1 in ASD patients. This study is significant as it is the first study to measure peripheral NRG1 in ASD patients.

Effects of endogenous serum neuregulin-1ß on morbidity and mortality in patients with heart failure and left ventricular systolic dysfunction.

CONTEXT: Improved left ventricular ejection fraction (LVEF) following administration of recombinant human Neuregulin-1ß (NRG), epidermal growth factor (EGF) involved in cardiomyocyte repair/survival, has been observed in patients with systolic heart failure (HF). METHODS: Serum NRG was measured by ELISA in 248 patients with NYHA class I-IV HF. RESULTS: NRG exhibited a marginally significant effect on LVEF trajectory over 11 months (p = 0.07). There is no apparent level of NRG that predicts improved survival. CONCLUSIONS: There is a potential relationship between serum NRG and improved LVEF, indicating the need to investigate the utility of NRG in predicting HF outcomes, including LVEF maintenance.

Neuregulin 1 (NRG1) gene expression predicts functional outcomes in individuals at clinical high-risk for psychosis.

Little is known about valid predictive markers for functional outcomes in an at-risk for psychosis population. In a cohort of 185 individuals (age: 13-35 years) at high risk (HR) and ultra-high risk (UHR), we assessed pan-NRG1 mRNA levels across good functional status (GFS) and poor functional status (PFS) at baseline, and good functional outcome (GFO) and poor functional outcome (PFO) at 12-month follow-up. NRG1 mRNA levels were significantly higher in individuals with PFO than individuals with GFO at 12-month follow-up. Our findings suggest that NRG1 might emerge as a predictive marker for functional outcomes in at-risk for psychosis population.

Soluble Neuregulin1 is strongly up-regulated in the rat model of Charcot-Marie-Tooth 1A disease.

Neuregulin1 (NRG1) is a growth factor playing a pivotal role in peripheral nerve development through the activation of the transmembrane co-receptors ErbB2-ErbB3. Soluble NRG1 isoforms, mainly secreted by Schwann cells, are strongly and transiently up-regulated after acute peripheral nerve injury, thus suggesting that they play a crucial role also in the response to nerve damage. Here we show that in the rat experimental model of the peripheral demyelinating neuropathy Charcot-Marie-Tooth 1A (CMT1A) the expression of the different NRG1 isoforms (soluble, type α and ß, type a and b) is strongly up-regulated, as well as the expression of NRG1 co-receptors ErbB2-ErbB3, thus showing that CMT1A nerves have a gene expression pattern highly reminiscent of injured nerves. Because it has been shown that high concentrations of soluble NRG1 negatively affect myelination, we suggest that soluble NRG1 over-expression might play a negative role in the pathogenesis of CMT1A disease, and that a therapeutic approach, aimed to interfere with NRG1 activity, might be beneficial for CMT1A patients. Further studies will be necessary to test this hypothesis in animal models and to evaluate NRG1 expression in human patients. Impact statement Charcot-Marie-Tooth1A (CMT1A) is one of the most frequent inherited neurological diseases, characterized by chronic demyelination of peripheral nerves, for which effective therapies are not yet available. It has been recently proposed that the treatment with soluble Neuregulin1 (NRG1), a growth factor released by Schwann cells immediately after acute nerve injury, might be effective in CMT1A treatment. However, the expression of the different isoforms of endogenous NRG1 in CMT1A nerves has not been yet investigated. In this preliminary study, we demonstrate that different isoforms of soluble NRG1 are strongly over-expressed in CMT1A nerves, thus suggesting that a therapeutic approach based on NRG1 treatment should be carefully reconsidered. If soluble NRG1 is over-expressed also in human CMT1A nerves, a therapeutic approach aimed to inhibit (instead of stimulate) the signal transduction pathways driven by NRG1 might be fruitfully developed. Further studies will be necessary to test these hypotheses.

Elevated peripheral expression of neuregulin-1 (NRG1) mRNA isoforms in clozapine-treated schizophrenia patients.

Differential expression of neuregulin-1 (NRG1) mRNA isoforms and proteins has been reported in schizophrenia, primarily in post-mortem brain tissue. In this study, we examined 12 NRG1 SNPs, eight NRG1 mRNA isoforms (type I, type I(Ig2), type II, type III, type IV, EGFα, EGFß, pan-NRG1) in whole blood, and NRG1-ß1 protein in serum of clozapine-treated schizophrenia patients (N = 71) and healthy controls (N = 57). In addition, using cultured peripheral blood mononuclear cells (PBMC) from 15 healthy individuals, we examined the effect of clozapine on NRG1 mRNA isoform and protein expression. We found elevated levels of NRG1 mRNA, specifically the EGFα (P = 0.0175), EGFß (P = 0.002) and type I(Ig2) (P = 0.023) containing transcripts, but lower NRG1-ß1 serum protein levels (P = 0.019) in schizophrenia patients compared to healthy controls. However, adjusting for smoking status attenuated the difference in NRG1-ß1 serum levels (P = 0.050). Examination of clinical factors showed NRG1 EGFα (P = 0.02) and EGFß (P = 0.02) isoform expression was negatively correlated with age of onset. However, we found limited evidence that NRG1 mRNA isoform or protein expression was associated with current chlorpromazine equivalent dose or clozapine plasma levels, the latter corroborated by our PBMC clozapine exposure experiment. Our SNP analysis found no robust expression quantitative trait loci. Our results represent the first comprehensive investigation of NRG1 isoforms and protein expression in the blood of clozapine-treated schizophrenia patients and suggest levels of some NRG1 transcripts are upregulated in those with schizophrenia.

Circulating neuregulin-1 and galectin-3 can be prognostic markers in breast cancer.

BACKGROUND: It is important to identify novel plasmatic biomarkers that can contribute to assessing the prognosis and outcome of breast cancer patients. Neuregulin-1 (NRG1) and galectin-3 (Gal-3) are proteins that are involved in breast cancer development and patient survival; therefore, we studied whether the serum concentration of these 2 proteins can be correlated to breast cancer progression. METHODS: Plasmatic NRG1 and Gal-3 were evaluated in 25 healthy controls and 50 breast cancer patients at baseline and at 3 and 6 months after treatment with anthracyclines and taxanes, with or without trastuzumab. RESULTS: NRG1 and Gal-3 were significantly more elevated in cancer patients than in healthy controls; furthermore, NRG1 and Gal-3 were significantly increased after chemotherapy and were predictive of mortality at 1 year. CONCLUSIONS: Circulating NRG1 and Gal-3 can be additional biomarkers indicative of prognosis and outcomes for breast cancer patients.

Circulating heregulin level is associated with the efficacy of patritumab combined with erlotinib in patients with non-small cell lung cancer.

OBJECTIVES: Patritumab is a fully human anti-human epidermal growth factor receptor 3 (HER3) antibody that blocks activation by its ligand, heregulin (HRG). Preclinical studies have demonstrated the efficacy of patritumab in aberrantly high HRG-expressing non-small cell lung cancer (NSCLC). In the phase II randomized, placebo-controlled double-blind study HERALD (n=212 patients with NSCLC), patritumab plus erlotinib did not improve progression-free survival (PFS) compared with placebo plus erlotinib. The current study examined whether soluble HRG (sHRG) level in serum correlated with the efficacy of patritumab plus erlotinib. MATERIALS AND METHODS: Serum was obtained from participants prior to treatment (n=202). sHRG level was measured using a validated quantitative immune assay, and correlations with survival were blindly assessed. RESULTS: sHRG level was various (-1346-11,772pg/mL). Participants were divided into the sHRG-high or -low subgroups at the concentration defining near the third quartile, 980pg/mL. Patritumab plus erlotinib significantly improved PFS relative to placebo in the sHRG-high subgroup (n=46, hazard ratio 0.42 [0.19-0.96], p=0.0327). In contrast, the HRG-low subgroup (n=148) had no improvement in PFS with patritumab. CONCLUSION: sHRG seems to be a predictive biomarker for the efficacy of patritumab plus erlotinib in NSCLC patients.