Effects of maternal folic acid supplementation during the second and third trimesters of pregnancy on neurocognitive development in the child: an 11-year follow-up from a randomised controlled trial.

BACKGROUND: Maternal folic acid (FA) supplementation before and in early pregnancy prevents neural tube defects (NTD), but it is uncertain whether continuing FA after the first trimester has benefits on offspring health. We aimed to evaluate the effect of FA supplementation throughout pregnancy on cognitive performance and brain function in the child. METHODS: Follow-up investigation of 11-year-old children, residing in Northern Ireland, whose mothers had participated in a randomised trial of Folic Acid Supplementation in the Second and Third Trimesters (FASSTT) in pregnancy and received 400 µg/day FA or placebo from the 14th gestational week. Cognitive performance (Full Scale Intelligence Quotient, Verbal Comprehension, Working Memory, Perceptual Reasoning, and Processing Speed) was assessed using the Wechsler Intelligence Scale for Children. Neuronal function was assessed using magnetoencephalographic (MEG) brain imaging. RESULTS: Of 119 mother-child pairs in the FASSTT trial, 68 children were assessed for neurocognitive performance at 11-year follow-up (Dec 2017 to Nov 2018). Children of mothers randomised to FA compared with placebo scored significantly higher in two Processing Speed tests, i.e. symbol search (mean difference 2.9 points, 95% CI 0.3 to 5.5, p = 0.03) and cancellation (11.3 points, 2.5 to 20.1, p = 0.04), whereas the positive effect on Verbal Comprehension was significant in girls only (6.5 points, 1.2 to 11.8, p = 0.03). MEG assessment of neuronal responses to a language task showed increased power at the Beta (13-30 Hz, p = 0.01) and High Gamma (49-70 Hz, p = 0.04) bands in children from FA-supplemented mothers, suggesting more efficient semantic processing of language. CONCLUSIONS: Continued FA supplementation in pregnancy beyond the early period currently recommended to prevent NTD can benefit neurocognitive development of the child. MEG provides a non-invasive tool in paediatric research to objectively assess functional brain activity in response to nutrition and other interventions. TRIAL REGISTRATION: ISRCTN ISRCTN19917787 . Registered on 15 May 2013.

Dynamic relationships between phonological memory and reading: A five year longitudinal study from age 4 to 9.

We reconcile competing theories of the role of phonological memory in reading development, by uncovering their dynamic relationship during the first 5 years of school. Phonological memory, reading and phoneme awareness were assessed in 780 phonics-educated children at age 4, 5, 6 and 9. Confirmatory factor analyses demonstrated that phonological memory loaded onto two factors: verbal short-term memory (verbal STM; phonological tasks that loaded primarily on serial order memory) and nonword repetition. Using longitudinal structural equation models, we found that verbal STM directly predicted early word-level reading from age 4 to 6, reflecting the importance of serial-order memory for letter-by-letter decoding. In contrast, reading had no reciprocal influence on the development of verbal STM. The relationship between nonword repetition and reading was bidirectional across the 5 years of study: nonword repetition and reading predicted each other both directly and indirectly (via phoneme awareness). Indirect effects from nonword repetition (and verbal STM) to reading support the view that phonological memory stimulates phonemically detailed representations through repeated encoding of complex verbal stimuli. Similarly, the indirect influence of reading on nonword repetition suggests that improved reading ability promotes the phoneme-level specificity of phonological representations. Finally, the direct influence from reading to nonword repetition suggests that better readers use orthographic cues to help them remember and repeat new words accurately. A video abstract of this article can be viewed at https://www.youtube.com/watch?v=70LZfTR0BjE.

Comparison of beamformer implementations for MEG source localization.

Beamformers are applied for estimating spatiotemporal characteristics of neuronal sources underlying measured MEG/EEG signals. Several MEG analysis toolboxes include an implementation of a linearly constrained minimum-variance (LCMV) beamformer. However, differences in implementations and in their results complicate the selection and application of beamformers and may hinder their wider adoption in research and clinical use. Additionally, combinations of different MEG sensor types (such as magnetometers and planar gradiometers) and application of preprocessing methods for interference suppression, such as signal space separation (SSS), can affect the results in different ways for different implementations. So far, a systematic evaluation of the different implementations has not been performed. Here, we compared the localization performance of the LCMV beamformer pipelines in four widely used open-source toolboxes (MNE-Python, FieldTrip, DAiSS (SPM12), and Brainstorm) using datasets both with and without SSS interference suppression. We analyzed MEG data that were i) simulated, ii) recorded from a static and moving phantom, and iii) recorded from a healthy volunteer receiving auditory, visual, and somatosensory stimulation. We also investigated the effects of SSS and the combination of the magnetometer and gradiometer signals. We quantified how localization error and point-spread volume vary with the signal-to-noise ratio (SNR) in all four toolboxes. When applied carefully to MEG data with a typical SNR (3-15 â€‹dB), all four toolboxes localized the sources reliably; however, they differed in their sensitivity to preprocessing parameters. As expected, localizations were highly unreliable at very low SNR, but we found high localization error also at very high SNRs for the first three toolboxes while Brainstorm showed greater robustness but with lower spatial resolution. We also found that the SNR improvement offered by SSS led to more accurate localization.

Auditory frequency discrimination in developmental dyslexia: A meta-analysis.

Auditory frequency discrimination has been used as an index of sensory processing in developmental language disorders such as dyslexia, where group differences have often been interpreted as evidence for a basic deficit in auditory processing that underpins and constrains individual variability in the development of phonological skills. Here, we conducted a meta-analysis to evaluate the cumulative evidence for group differences in frequency discrimination and to explore the impact of some potential moderator variables that could contribute to variability in effect-size estimations across studies. Our analyses revealed mean effect sizes for group differences on frequency discrimination tasks on the order of three-quarters of a standard deviation, but in the presence of substantial inter-study variability in their magnitude. Moderator variable analyses indicated that factors related both to participant variability on behavioural and cognitive variables associated with the dyslexia phenotype, and to variability in the task design, contributed to differences in the magnitude of effect size across studies. The apparently complex pattern of results was compounded by the lack of concurrent, standardised metrics of cognitive and reading component skills across the constituent studies. Differences on sensory processing tasks are often reported in studies of developmental disorders, but these need to be more carefully interpreted in the context of non-sensory factors, which may explain significant inter- and intra-group variance in the dependent measure of interest.

Behavioral and Molecular Genetics of Reading-Related AM and FM Detection Thresholds.

Auditory detection thresholds for certain frequencies of both amplitude modulated (AM) and frequency modulated (FM) dynamic auditory stimuli are associated with reading in typically developing and dyslexic readers. We present the first behavioral and molecular genetic characterization of these two auditory traits. Two extant extended family datasets were given reading tasks and psychoacoustic tasks to determine FM 2 Hz and AM 20 Hz sensitivity thresholds. Univariate heritabilities were significant for both AM (h 2  = 0.20) and FM (h 2  = 0.29). Bayesian posterior probability of linkage (PPL) analysis found loci for AM (12q, PPL = 81 %) and FM (10p, PPL = 32 %; 20q, PPL = 65 %). Bivariate heritability analyses revealed that FM is genetically correlated with reading, while AM was not. Bivariate PPL analysis indicates that FM loci (10p, 20q) are not also associated with reading.

Magnetoencephalography in the study of epilepsy and consciousness.

The neural bases of altered consciousness in patients with epilepsy during seizures and at rest have raised significant interest in the last decade. This exponential growth has been supported by the parallel development of techniques and methods to investigate brain function noninvasively with unprecedented spatial and temporal resolution. In this article, we review the contribution of magnetoencephalography to deconvolve the bioelectrical changes associated with impaired consciousness during seizures. We use data collected from a patient with refractory absence seizures to discuss how spike-wave discharges are associated with perturbations in optimal connectivity within and between brain regions and discuss indirect evidence to suggest that this phenomenon might explain the cognitive deficits experienced during prolonged 3/s spike-wave discharges.

A novel binaural pitch elicited by phase-modulated noise: MEG and psychophysical observations.

Binaural pitches are auditory percepts that emerge from combined inputs to the ears but that cannot be heard if the stimulus is presented to either ear alone. Here, we describe a binaural pitch that is not easily accommodated within current models of binaural processing. Convergent magnetoencephalography (MEG) and psychophysical measurements were used to characterize the pitch, heard when band-limited noise had a rapidly changing interaural phase difference. Several interesting features emerged: First, the pitch was perceptually lateralized, in agreement with the lateralization of the evoked changes in MEG spectral power, and its salience depended on dichotic binaural presentation. Second, the frequency of the pure tone that matched the binaural pitch lay within a lower spectral sideband of the phase-modulated noise and followed the frequency of that sideband when the modulation frequency or center frequency and bandwidth of the noise changed. Thus, the binaural pitch depended on the processing of binaural information in that lower sideband.

Anatomical correlates of dynamic auditory processing: relationship to literacy during early adolescence.

Adults show great variation in their auditory skills, such as being able to discriminate between foreign speech-sounds. Previous research has demonstrated that structural features of auditory cortex can predict auditory abilities; here we are interested in the maturation of 2-Hz frequency-modulation (FM) detection, a task thought to tap into mechanisms underlying language abilities. We hypothesized that an individual's FM threshold will correlate with gray-matter density in left Heschl's gyrus, and that this function-structure relationship will change through adolescence. To test this hypothesis, we collected anatomical magnetic resonance imaging data from participants who were tested and scanned at three time points: at 10, 11.5 and 13 years of age. Participants judged which of two tones contained FM; the modulation depth was adjusted using an adaptive staircase procedure and their threshold was calculated based on the geometric mean of the last eight reversals. Using voxel-based morphometry, we found that FM threshold was significantly correlated with gray-matter density in left Heschl's gyrus at the age of 10 years, but that this correlation weakened with age. While there were no differences between girls and boys at Times 1 and 2, at Time 3 there was a relationship between gray-matter density in left Heschl's gyrus in boys but not in girls. Taken together, our results confirm that the structure of the auditory cortex can predict temporal processing abilities, namely that gray-matter density in left Heschl's gyrus can predict 2-Hz FM detection threshold. This ability is dependent on the processing of sounds changing over time, a skill believed necessary for speech processing. We tested this assumption and found that FM threshold significantly correlated with spelling abilities at Time 1, but that this correlation was found only in boys. This correlation decreased at Time 2, and at Time 3 we found a significant correlation between reading and FM threshold, but again, only in boys. We examined the sex differences in both the imaging and behavioral data taking into account pubertal stages, and found that the correlation between FM threshold and spelling was strongest pre-pubertally, and the correlation between FM threshold and gray-matter density in left Heschl's gyrus was strongest mid-pubertally.

Molecular alterations in AKT1, AKT2 and AKT3 detected in breast and prostatic cancer by FISH.

AIMS: The AKT family is implicated in cancer progression. There are three mammalian AKT isoforms located on chromosomes 14, 19 and 1, respectively. The aim of the study was to investigate genetic alterations of AKT in breast and prostatic cancers using fluorescence in situ hybridization (FISH). METHODS AND RESULTS: In oestrogen receptor(ER)-positive breast carcinomas, AKT1 was deleted in five (4.8%) and amplified in one (1%) carcinoma. Deletions of AKT2 were seen in 19 (21.1%) cases. No AKT2 amplifications were identified. Ten (9.9%) AKT3 amplifications but no deletions were seen. In prostatic cancer, AKT1 was amplified in one carcinoma (2.6%). No genetic changes were observed for AKT2 and AKT3. High frequencies of aneusomy for all chromosomes were observed in breast and prostatic carcinomas. CONCLUSIONS: In breast cancer AKT3 amplifications and AKT1 and AKT2 deletions were seen, which, to our knowledge, have not been shown by FISH before. Although these two cohorts cannot be directly compared, only one AKT1 amplification was identified in prostatic carcinomas. This indicates differences in the genetic changes underlying development of breast and prostatic cancers. To evaluate further the role of genetic changes of AKT in breast cancer progression, a cohort of both ER+ and ER- patients should be evaluated.

Childhood auditory processing disorder as a developmental disorder: the case for a multi-professional approach to diagnosis and management.

Auditory processing disorder (APD) is diagnosed when a patient presents with listening difficulties which can not be explained by a peripheral hearing impairment or higher-order cognitive or language problems. This review explores the association between auditory processing disorder (APD) and other specific developmental disorders such as dyslexia and attention-deficit hyperactivity disorder. The diagnosis and aetiology of APD are similar to those of other developmental disorders and it is well established that APD often co-occurs with impairments of language, literacy, and attention. The genetic and neurological causes of APD are poorly understood, but developmental and behavioural genetic research with other disorders suggests that clinicians should expect APD to co-occur with other symptoms frequently. The clinical implications of co-occurring symptoms of other developmental disorders are considered and the review concludes that a multi-professional approach to the diagnosis and management of APD, involving speech and language therapy and psychology as well as audiology, is essential to ensure that children have access to the most appropriate range of support and interventions.

Symptoms of hyperactivity and inattention can mediate deficits of postural stability in developmental dyslexia.

Developmental dyslexia is a reading disorder associated with impaired postural control. However, such deficits are also found in attention deficit hyperactivity disorder (ADHD), which is present in a substantial subset of dyslexia diagnoses. Very few studies of balance in dyslexia have assessed ADHD symptoms, thereby motivating the hypothesis that such measures can account for the group differences observed. In this study, we assessed adults with dyslexia and similarly aged controls on a battery of cognitive, literacy and attention measures, alongside tasks of postural stability. Displacements of centre of mass to perturbations of posture were measured in four experimental conditions using digital optical motion capture. The largest group differences were obtained in conditions where cues to the support surface were reduced. Between-group differences in postural sway and in sway variability were largely accounted for by co-varying hyperactivity and inattention ratings, however. These results therefore suggest that postural instability in dyslexia is more strongly associated with symptoms of ADHD than to those specific to reading impairment.

Rogue bioelectrical waves in the brain: the Hurst exponent as a potential measure for presurgical mapping in epilepsy.

OBJECTIVE: Brain electromagnetic activity in patients with epilepsy is characterized by abnormal high-amplitude transient events (spikes) and abnormal patterns of synchronization of brain rhythms that accompany epileptic seizures. With the aim of improving methods for identifying epileptogenic sources in magnetoencephalographic (MEG) recordings of brain data, we applied methods previously used in the study of oceanic 'rogue waves' and other freak events in complex systems. APPROACH: For data from three patients who were awaiting surgical treatment for epilepsy, we used a beamformer source model to produce volumetric maps showing areas with a high proportion of spikes that could be classified as 'rogue waves', and areas with high Hurst exponent (HE). The HE describes the extent to which a system is exhibiting persistent behavior, may predict the likelihood of freak events. These measures were compared with the more standard measure of kurtosis, which has been shown to be a reliable method for localizing interictal spikes. MAIN RESULTS: There was partial concordance between the three different volumetric maps indicating that each measure provides different information about the underlying brain data. The HE, when combined with a simple connectivity analysis based on phase slope index (PSI), was able to identify the probable epileptogenic zone in all three patients, despite very different patterns of abnormal activity. The differences between distributions of high HE and high kurtosis values indicates that while spikes are propagated through cortex from the epileptogenic zone, the persistent dynamical conditions under which the spikes are generated may not be propagated in a similar way. Finally, the patterns of persistent activity, indicating a departure from 'healthy criticality' in brain networks may explain the wide range of social and cognitive impairments that are seen in epilepsy patients. SIGNIFICANCE: The HE is a potentially useful addition to the clinician's battery of measures which may be used convergently to guide surgical intervention.

Prognostic significance of numeric aberrations of genes for thymidylate synthase, thymidine phosphorylase and dihydrofolate reductase in colorectal cancer.

BACKGROUND: Most human cancer cells have structural aberrations of chromosomal regions leading to loss or gain of gene specific alleles. This study aimed to assess the range of gene copies per nucleus of thymidylate synthase (TYMS), thymidine phosphorylase (TP) and dihydrofolate reductase (DHFR) in colorectal cancer, and to evaluate its prognostic significance following adjuvant chemotherapy, since these enzymes are closely related to efficacy of 5-fluorouracil (5FU). PATIENTS AND METHODS: Consecutive patients (n = 314), who were completely resected for colorectal cancer stages II-IV and adjuvantly treated with 5-FU were retrospectively evaluated. Paraffin embedded tumor specimens were assessed for gene copies per nucleus of TYMS, TP and DHFR by fluorescence in situ hybridisation (FISH) using specific peptide nucleic acid probes. Outcome according to gene copies per nucleus above and below the median were compared. Also TYMS expression, assessed by immunohistochemistry, was associated with TYMS copies per nucleus. RESULTS: The number of gene copies per nucleus were 1.7 (0.7-2.8), 1.8 (0.9-3.1) and 1.8 (1.1-2.7) median (range) for TYMS, TP and DHFR, respectively. TYMS expression was directly associated with TYMS genes per nucleus (p = 0.05). Cox multivariate analysis, adjusted for the prognostic impact of disease stage, vascular tumor invasion, and bowel obstruction at resection, revealed that high TYMS gene copy number was associated with significantly higher risk of recurrence (HR = 1.6; 95%CI 1.1-2.2; p = 0.02) and death (HR = 1.6; 95%CI 1.1-2.3; p = 0.01). No significant differences in outcome appeared according to TP and DHFR gene ratios. CONCLUSION: Aberration of TYMS gene is of significance to expression of TYMS, which may influence the biology and 5-FU sensitivity of colorectal cancer. This may be utilized in the allocation of patients for treatment approaches and for decision on follow-up programs.

Interhemispheric differences of spectral power in expressive language: a MEG study with clinical applications.

In the last decade we have seen an exponential growth of functional imaging studies investigating multiple aspects of language processing. These studies have sparked an interest in applying some of the paradigms to various clinically relevant questions, such as the identification of the cortical regions mediating language function in surgical candidates for refractory epilepsy. Here we present data from a group of adult control participants in order to investigate the potential of using frequency specific spectral power changes in MEG activation patterns to establish lateralisation of language function using expressive language tasks. In addition, we report on a paediatric patient whose language function was assessed before and after a left hemisphere amygdalo-hippocampectomy. Our verb generation task produced left hemisphere decreases in beta-band power accompanied by right hemisphere increases in low beta-band power in the majority of the control group, a previously unreported phenomenon. This pattern of spectral power was also found in the patient's post-surgery data, though not her pre-surgery data. Comparison of pre and post-operative results also provided some evidence of reorganisation in language related cortex both inter- and intra-hemispherically following surgery. The differences were not limited to changes in localisation of language specific cortex but also changes in the spectral and temporal profile of frontal brain regions during verb generation. While further investigation is required to establish concordance with invasive measures, our data suggest that the methods described may serve as a reliable lateralisation marker for clinical assessment. Furthermore, our findings highlight the potential utility of MEG for the investigation of cortical language functioning in both healthy development and pathology.

An evaluation of kurtosis beamforming in magnetoencephalography to localize the epileptogenic zone in drug resistant epilepsy patients.

OBJECTIVE: Kurtosis beamforming is a useful technique for analysing magnetoencephalograpy (MEG) data containing epileptic spikes. However, the implementation varies and few studies measure concordance with subsequently resected areas. We evaluated kurtosis beamforming as a means of localizing spikes in drug-resistant epilepsy patients. METHODS: We retrospectively applied kurtosis beamforming to MEG recordings of 22 epilepsy patients that had previously been analysed using equivalent current dipole (ECD) fitting. Virtual electrodes were placed in the kurtosis volumetric peaks and visually inspected to select a candidate source. The candidate sources were compared to the ECD localizations and resection areas. RESULTS: The kurtosis beamformer produced interpretable localizations in 18/22 patients, of which the candidate source coincided with the resection lobe in 9/13 seizure-free patients and in 3/5 patients with persistent seizures. The sublobar accuracy of the kurtosis beamformer with respect to the resection zone was higher than ECD (56% and 50%, respectively), however, ECD resulted in a higher lobar accuracy (75%, 67%). CONCLUSIONS: Kurtosis beamforming may provide additional value when spikes are not clearly discernible on the sensors and support ECD localizations when dipoles are scattered. SIGNIFICANCE: Kurtosis beamforming should be integrated with existing clinical protocols to assist in localizing the epileptogenic zone.

Psychophysical measurements in children: challenges, pitfalls, and considerations.

Measuring sensory sensitivity is important in studying development and developmental disorders. However, with children, there is a need to balance reliable but lengthy sensory tasks with the child's ability to maintain motivation and vigilance. We used simulations to explore the problems associated with shortening adaptive psychophysical procedures, and suggest how these problems might be addressed. We quantify how adaptive procedures with too few reversals can over-estimate thresholds, introduce substantial measurement error, and make estimates of individual thresholds less reliable. The associated measurement error also obscures group differences. Adaptive procedures with children should therefore use as many reversals as possible, to reduce the effects of both Type 1 and Type 2 errors. Differences in response consistency, resulting from lapses in attention, further increase the over-estimation of threshold. Comparisons between data from individuals who may differ in lapse rate are therefore problematic, but measures to estimate and account for lapse rates in analyses may mitigate this problem.

The auditory evoked-gamma response and its relation with the N1m.

This study explored the patterns of oscillatory activity that underpin the N1m auditory evoked response. Evoked gamma activity is a small and relatively rarely-reported component of the auditory evoked response, and the objective of this work was to determine how this component relates to the larger and more prolonged changes in lower frequency bands. An event-related beamformer analysis of MEG data from monaural click stimulation was used to reconstruct volumetric images and virtual electrode time series. Group analysis of localisations showed that activity in the gamma band originated from a source that was more medial than those for activity in the theta-to-beta band, and virtual-electrode analysis showed that the source of the gamma activity could be statistically dissociated from the lower-frequency response. These findings are in accordance with separate functional roles for the activity in each frequency band, and provide evidence that the oscillatory activity that underpins the auditory evoked response may contain important information about the physiological basis of the macroscopic signals recorded by MEG in response to auditory stimulation.

HER4 in breast cancer: comparison of antibodies against intra- and extra-cellular domains of HER4.

INTRODUCTION: We have previously linked HER4 expression with increased survival in breast cancer. However, other reports have associated HER4 with adverse prognostic significance. One possible explanation for the conflicting reports may be that these results are antibody dependent. The HER4 protein is enzymatically cleaved, which may alter the function of its intracellular domain (ICD). We have therefore compared the staining patterns of antibodies against its intracellular and extracellular domains using tissue microarray technology. METHODS: Immunohistochemistry was performed and evaluated on tumours from 402 tamoxifen treated oestrogen receptor positive patients. The HFR1 antibody recognises the ICD of HER4 and thus recognises both the intact receptor and the cleaved ICD. The H4.77.16 clone recognises an extracellular domain of HER4 and thus detects the full length receptor only. RESULTS: Both antibodies demonstrated nuclear, cytoplasmic and membranous staining. Concordance between the membrane staining patterns was high (88.44%, kappa 0.426). The HFR1 antibody, however, demonstrated generally higher levels of cytoplasmic staining (concordance 74.77%, kappa 0.351). The antibodies demonstrated very different patterns of nuclear staining. Over 60% of patients stained with the H4.77.16 had no nuclear staining whereas the vast majority showed staining with the HFR1 antibody (concordance 40.12%, kappa 0.051). Neither antibody demonstrated relationships between membranous or cytoplasmic HER4 staining and survival, although associations were seen with known poor prognostic markers. Cases with H4.77.16-determined nuclear staining had significantly poorer survival outcomes. CONCLUSION: The difference in antigen site may explain the different staining patterns we have seen with respect to location; with each antibody appearing to select for distinct compartments. Thus, HFR1 may select for cytoplasmic and nuclear HER4 ICD, whilst H4.77.16 selects for membranous HER4 and/or HER4 being recycled in cytoplasm or nucleus. This ability to distinguish between site and function of HER4 and its fragments is particularly important, with recent evidence highlighting the different functions of nuclear and mitochondrial HER4.

Abnormality of mismatch negativity in response to tone omission in dyslexic adults.

Evidence of abnormalities in the perception of rapidly presented sounds in dyslexia has been interpreted as evidence of a prolonged time window within which sounds can influence the perception of temporally surrounding sounds. We recorded the magnetic mismatch negativity (MMNm) to infrequent tone omissions in a group of six dyslexic adults and six IQ and age-matched controls. An MMNm is only elicited in response to a complete stimulus omission when successive inputs fall within the temporal window of integration (stimulus onset asynchrony (SOA) approximately 160 ms). No MMNm responses were recorded in either experimental group when stimuli were presented at SOAs falling just outside the temporal window of integration (SOA = 175 ms). However, while presentation rates of 100 ms resulted in MMNm responses for all control participants, the same stimulus omissions elicited an MMNm response in only one of the six dyslexic participants. These results cannot support the hypothesis of a prolonged time window of integration, but rather indicate auditory grouping deficits in the dyslexic population.

Can molecular markers predict when to implement treatment with aromatase inhibitors in invasive breast cancer?

PURPOSE: Resistance to tamoxifen is linked to overexpression of HER2, and aromatase inhibitors show particular benefit in progesterone receptor (PR)-negative patients. We previously reported reduced survival in patients overexpressing HER1, HER2, and HER3. We now show that both HER1-3 and PR status predicts for early relapse in estrogen receptor (ER)-positive tamoxifen-treated breast cancer patients. EXPERIMENTAL DESIGN: Tissue microarray technology was used to analyze 402 ER-positive tamoxifen-treated patients. Immunohistochemistry using epidermal growth factor receptor, HER2, HER3, HER4, and PR antibodies was done. Kaplan-Meier life table and Cox Regression analysis (log-rank testing of differences in breast cancer-related relapse on tamoxifen) was done. RESULTS: HER1-3 (but not HER4) overexpression predicted for early relapse on tamoxifen (P = 0.0060). PR-negative cases were also significantly more likely to relapse while on tamoxifen (P= 0.017). HER1-3-positive and/or PR-negative patients combined as a "high-risk" group were significantly more likely to relapse on tamoxifen in univariate (P < 0.0001) and Cox's multivariate analysis (P = 0.0069). However, this applied to early relapse on tamoxifen only, as any disease relapse after 3 years of tamoxifen was unrelated to PR/HER status. CONCLUSIONS: We show that HER1-3 and PR status can identify time-dependent de novo tamoxifen resistance with risk declining markedly after 3 years of tamoxifen treatment. These results parallel data from the ATAC and Intergroup Exemastane Study trials which suggest that whereas PR-negative patients derive greater benefit from initial aromatase inhibitor treatment, PR status has no effect on response when given as delayed treatment to those disease free on tamoxifen after 3 years.