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Background: HER3 is thought to play a prominent role in resistance to HER2-directed breast cancer therapies. Recent data suggest that HER3 levels also influence HER2-normal breast tumor biology. HER3 and PI3K signaling are linked in that in HER3 signaling activates PI3K and inhibition of PI3K activity can upregulate HER3 expression. Here, we measured quantitative HER3 protein expression levels and PIK3CA mutation status in matched tissues from the primary tumor and site of metastasis to assess correlations with time to recurrence. Methods: 44 pairs (8 HER2+ by HERmark®) of matched tissues from the primary tumor and the site of metastasis were evaluated for HER3 protein expression using a sensitive, quantitative assay for HER3 protein expression in FFPE tissue sections (VeraTag®). Matched samples were also evaluated for quantitative HER2 expression (HERmark) and for PIK3CA mutations at exon 9 (E542K and E545K) and exon 20 (H1047R). Results: HER3 protein expression at the metastatic site was largely independent of HER3 levels at the primary site (Spearman p = 0.50) in contrast to HER2 expression (Spearman p = 0.0004). HER3 expression in the primary tumor correlated with time to recurrence (TTR) (HR = 2.0 per 2-fold increase in HER3; p < 0.0001). Conversely, HER3 expression measured at the site of metastasis was not correlated with TTR (p = 0.55). Estrogen receptor negative tumors were less likely to have PIK3CA mutations (p = 0.023). In cases of primary tumors with PIK3CA mutations, no reversions to wild-type PIK3CA were observed in the metastatic sites. In metastatic tumors, mutations detected in the primary tumor as well as new mutations were observed. A gain of an exon 9 mutation at the metastatic site correlated with shorter TTR (HR = 2.5; p = 0.043). Excluding the 8 samples that were HER2+ by HERmark, longer TTR was observed for patients with PIK3CA mutations in the primary tumor (HR = 0.47; p = 0.042), which is consistent with previous reports. Interestingly, the longer TTR for those with PIK3CA mutations appeared to be dependent on quantitative HER3 protein level (interaction p = 0.065). Conclusions: HER3 protein expression in matched primary and metastatic breast cancer tissues were unrelated. This may indicate that HER3 protein is influenced by the different tumor microenvironments of the primary and metastatic sites. PIK3CA mutations were either maintained or acquired at metastatic sites. Both low HER3 protein expression and the presence of PIK3CA mutations in the primary tumor but not the metastatic tumor were associated with longer TTR. These observations suggest that HER3 protein expression may be an important prognostic factor for breast cancer progression. [ABSTRACT FROM AUTHOR]

Methods: 232 FFPE breast cancer tissues were provided by 11 CBS study sites for HER2 testing by the HERmark assay and central laboratory IHC re-testing performed in blinded fashion. Local HER2 immunohistochemistry and/or fluorescence in situ hybridization (FISH) results and valid HERmark H2T and central HER2 IHC results were obtained in 192 cases for analysis. Results: H2T showed a significant correlation with central HER2 IHC staining intensity (P < 0.0001). The concordance rates of positive and negative HERmark status (excluding equivocal) with those of local HER2 status determined by the CBS sites, and with those of central HER2 IHC status were 84% (Kappa = 0.68) and 96% (Kappa = 0.91), respectively. Higher H2T levels significantly correlated with higher tumor grade (p = 0.007) and negative ER/PR status (p = 0.002). Twenty-six (14%) cases showed discordant (conversion of negative and positive) results between local HER2 status and HERmark status. Of the discordant cases, HERmark significantly agreed with H-score of central HER2 IHC retesting (p = 0.014), as compared with local HER2 status. The concordant negative group (local HER2 negative/H2T low) demonstrated better overall survival (OS) (HR = 0.198, p = 0.0001), compared to that of concordant positive group (local HER2 positive/H2T high). The concordant negative group also showed better OS than that of discordant local HER2 negative/H2T high group (HR = 0.065, p = 0.0003), but showed no significant difference in OS as compared to that of discordant local HER2 positive/H2T low group (HR = 1.774, p = 0.499).). In 24 cases (13%) considered to be "triple negative" by local HER2, ER and PR testing, HERmark re-classified 4 cases (17%) as HER2 positive. Conclusions: H2T by HERmark yields a continuum of quantitative HER2 protein measurements that shows an excellent correlation with central HER2 IHC retesting and confirms the known correlations between HER2 expression with tumor grade and ER/PR status. OS results of concordant HER2 positive or negative groups (between local HER2 testing and HERmark H2T) confirmed that HER2 positive patients (excluding adjuvant trastuzumab therapy) have worse OS than patients with HER2 negative disease. However, in the HERmark and local HER2 discordant groups, OS appeared to track better with H2T by HERmark and not with the local HER2 status. Novel quantitative HER2 measurements may identify patients with false (+) and (-) HER2 status by local HER2 testing and may provide added clinical value to routine "real world" HER2 testing. [ABSTRACT FROM AUTHOR]

Background: Minoritized communities in the United States have had higher COVID-19 mortality and lower vaccine uptake. The influence of previous SARS-CoV-2 infection, initial disease severity, and persistent symptoms on COVID-19 vaccine uptake in Black and Latinx communities has not been examined., Objective: To investigate whether initial COVID-19 severity, persistent symptoms, and other correlates affected vaccine uptake in a predominantly minoritized cohort hospitalized for COVID-19 during the early pandemic in New York City., Design: In this historical cohort study, we abstracted electronic health record data on demographics, comorbidities, hospital oxygen requirements, symptoms at 3 and 6 months post-admission, COVID-19 vaccinations through November 2022, and influenza vaccinations during the 2018-2019 through 2021-2022 seasons. Unadjusted and adjusted odds ratios were estimated through logistic regression analyses of correlates of COVID-19 vaccination, on-time vaccination, and boosting., Participants: Survivors among the first 1186 adult patients hospitalized for COVID-19 between March 1 and April 8, 2020 at a large quaternary care medical center in Northern Manhattan., Main Measures: Uptake of at least one COVID-19 vaccine dose, uptake of at least one booster, and on-time vaccination., Key Results: The 890 surviving individuals were predominantly Latinx (54%) and Non-Hispanic Black (15%). Most had one or more comorbidities (67%), and received at least one COVID-19 vaccine dose (78%). Among those vaccinated, 57% received at least one booster, and 31% delayed vaccination. 67% experienced persistent symptoms. Multiple logistic regression showed no association between vaccine uptake and disease severity or symptom persistence. However, older age and influenza vaccination during the COVID-19 era were associated with increased vaccination, booster uptake, and on-time vaccination., Conclusions: Pinpointing drivers of vaccine uptake and hesitancy is critical to increasing and sustaining COVID-19 vaccination as the field transitions to annual boosters. The association between influenza vaccination and increased vaccine uptake suggests that bundling vaccines for adults may be an effective delivery strategy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Delivette Castor and Magdalena Sobieszczyk report financial support was provided by Gilead Sciences, Inc. Magdalena Sobieszczyk reports a relationship with Bill & Melinda Gates Foundation that includes: funding grants. Magdalena Sobieszczyk reports a relationship with Merck & Co Inc. that includes: funding grants. Magdalena Sobieszczyk reports a relationship with Sanofi that includes: funding grants. Magdalena Sobieszczyk reports a relationship with Pfizer Inc. that includes: funding grants. Jason Zucker reports a relationship with Centers for Disease Control and Prevention that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. JZ has received a grant from the Centers for Disease Control and Prevention within the past 3 years. MES has received grants from the Gates Foundation, Merck, Sanofi, and Pfizer within the past 3 years for work outside the scope of this manuscript. Otherwise, the authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Chemoreception and recognition of specific prey are important sensory modalities for optimizing foraging success in snakes. Field observations suggest that cottonmouths are generalists, despite the specific epithet of the species ( piscivorus ) suggesting a fish prey preference. Because chemo-recognition of specific prey may reveal interesting evolutionary context for foraging strategy and if prey preference is either genetically or environmentally controlled, we investigated the prey cue preference of three experimental groups of Agkistrodon piscivorus (Northern Cottonmouths) with different diet histories. Two groups of captive snakes were acclimated to year-long diets of either fish ( n  = 11) or mice ( n  = 9) and a third group of recently wild-caught individuals served as a field diet group ( n  = 16). We investigated possible differences among diet history (fish, mouse, and field) and prey cue preference (control, fish, and mouse) and present results showing a significant difference among diet history with field snakes having significantly lower tongue-flick response. We also found a significant difference among prey cues, snakes within all diet histories showed a lower tongue-flick response to only the control scent cue. Both captive and field snakes showed no prey cue preference for either fish or mice. Because captive snakes did not show increased prey cue preference to their respective diet history, prey preference may be under genetic influence and not experience-based. Additionally, the lack of prey preference for fish or mice in the recently captured snakes in the field-diet group provides supporting evidence that A. piscivorus are generalists and opportunistic predators., Competing Interests: The authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology.)

Background: Use of fine-needle aspiration biopsy (FNAB) specimens on Xpert Breast Cancer STRAT4 Assay (STRAT4; Cepheid, Sunnyvale, CA, USA), a CE-marked in-vitro diagnostic medical device, could potentially increase access to breast cancer biomarker testing in resource-constrained settings. We aimed to assess the performance of a research use-only version of STRAT4 using FNAB specimens in Tanzania., Methods: In this prospective diagnostic accuracy study, patients aged 18 years or older with palpable breast masses presenting to the FNAB Clinic at Muhimbili National Hospital (Dar es Salaam, Tanzania) were recruited consecutively. Patients who were pregnant, lactating, or had a previous diagnosis of breast cancer were excluded. STRAT4 testing was performed on off-label FNAB samples using four protocols: the 1 × protocol (using the standard lysate method) on FNAB smears (1 × FNAB), quick lysis and Maui protocols (both on FNAB smears), and the 1 × protocol on formalin-fixed paraffin-embedded (FFPE) cell block material (1 × cell block). For 1 × FNAB and 1 × cell block, tissue was processed using FFPE lysis reagent, incubated at 80°C with proteinase K, and followed by addition of 95% or higher ethanol. Quick lysis was processed using FFPE lysis reagent and 95% or higher ethanol, whereas Maui was processed using a proprietary research-use only lysis reagent. The primary outcomes were overall concordance, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) of STRAT4 as compared with immunohistochemistry or immunohistochemistry plus fluorescence in-situ hybridisation performed on cell blocks using clinically validated protocols in a Clinical Laboratory Improvement Amendments-accredited laboratory at the University of California, San Francisco (San Francisco, CA, USA)., Findings: Between Nov 29, 2017, and Dec 17, 2020, 208 patients were enrolled. Of 208 cases, 51 (25%) were excluded from analysis because of insufficient tissue in the cell block or absent cell blocks, leaving 157 participants (all female) for analysis. For oestrogen receptor, 1 × FNAB had the best performance, with an overall concordance of 95% (95% CI 90-100), sensitivity of 94% (85-100), specificity of 97% (90-100), and AUC of 0·96 (0·81-1·00). For progesterone receptor, 1 × cell block had the best overall performance (overall concordance 89% [95% CI 84-95], sensitivity 91% [82-99], and specificity 89% [81-97], with an AUC of 0·93 [0·89-0·99]) and 1 × FNAB performed the best among the smear protocols, with a concordance of 84% (95% CI 74-93), sensitivity of 63% (43-82), specificity of 97% (92-100), and AUC of 0·91 (0·72-0·97). For HER2, Maui had the highest agreement, with an overall concordance of 93% (95% CI 89-98), sensitivity of 96% (88-100), specificity of 92% (87-98), and AUC of 0·95 (0·98-1·00). For Ki67, Maui had the best performance of smear protocols, with a concordance of 73% (95% CI 64-82), sensitivity of 70% (58-81), specificity of 81% (66-96), and AUC of 0·80 (0·54-0·82)., Interpretation: Processing FNAB samples with STRAT4 is feasible in Tanzania, and performance for the oestrogen receptor is robust. Further optimisation of STRAT4 for FNAB has the potential to improve timely access to breast cancer diagnostics in resource-constrained settings., Funding: US National Institutes of Health; UCSF Global Cancer Program, Helen Diller Family Comprehensive Cancer Center; UCSF Department of Pathology; and Cepheid., Competing Interests: Declaration of interests KEH, JW, and MB are employees of Cepheid and own stock shares in Cepheid's parent company, Danaher. DLN and EV received funding, equipment, and study materials for the project from Cepheid. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Overexpression of human epidermal growth factor receptor 2 (HER2) caused by HER2 gene amplification is a driver in breast cancer tumorigenesis. We aimed to investigate the prognostic significance of manual scoring and digital image analysis (DIA) algorithm assessment of HER2 copy numbers and HER2/CEP17 ratios, along with ERBB2 mRNA levels among early-stage HER2-positive breast cancer patients treated with trastuzumab., Methods: This retrospective study comprised 371 early HER2-positive breast cancer patients treated with adjuvant trastuzumab, with HER2 re-testing performed on whole tumor sections. Digitized tumor tissue slides were manually scored and assessed with uPath HER2 Dual ISH image analysis, breast algorithm. Targeted ERBB2 mRNA levels were assessed by the Xpert® Breast Cancer STRAT4 Assay. HER2 copy number and HER2/CEP17 ratio from in situ hybridization assessment, along with ERBB2 mRNA levels, were explored in relation to recurrence-free survival (RFS)., Results: The analysis showed that patients with tumors with the highest and lowest manually counted HER2 copy number levels had worse RFS than those with intermediate levels (HR = 2.7, CI 1.4-5.3, p = 0.003 and HR = 2.1, CI 1.1-3.9, p = 0.03, respectively). A similar trend was observed for HER2/CEP17 ratio, and the DIA algorithm confirmed the results. Moreover, patients with tumors with the highest and the lowest values of ERBB2 mRNA had a significantly worse prognosis (HR = 2.7, CI 1.4-5.1, p = 0.003 and HR = 2.8, CI 1.4-5.5, p = 0.004, respectively) compared to those with intermediate levels., Conclusions: Our findings suggest that the association between any of the three HER2 biomarkers and RFS was nonlinear. Patients with tumors with the highest levels of HER2 gene amplification or ERBB2 mRNA were associated with a worse prognosis than those with intermediate levels, which is of importance to investigate in future clinical trials studying HER2-targeted therapy., (© 2024. The Author(s).)