Long term survival achieved through combination of almonertinib and pyrotinib in EGFR-mutant/HER2-amplified advanced NSCLC patient: a case report and literature review.

Backgroud: Human epithelial growth factor receptor 2 (HER2) amplification is an important mechanism of acquired resistance to anti-epidermal growth factor receptor (EGFR) therapy in non-small cell lung cancer (NSCLC) patients. For patients with both EGFR mutation and HER2 amplification, there is currently no unified standard treatment, and further exploration is needed on how to choose the therapy. Methods and results: A female NSCLC patient developed bone and brain metastases 14 and 42 months after radical surgery, respectively. The second genetic sequencing detected EGFR L858R mutation and HER2 amplification, and therefore initiated treatment with almonertinib and pyrotinib. The patient achieved partial remission and did not show any further progression during the follow-up period. Conclusion: For NSCLC patients with both EGFR mutation and HER2 amplification, the combination of almonertinib and pyrotinib is a valuable therapy that can continuously reduce tumor burden and achieve long-term survival.

Causal role of blood metabolites in HER-positive and HER-negative breast cancer: a Mendelian randomization (MR) study.

BACKGROUND: Previous studies provide evidence that in vivo metabolites are associated with breast cancer (BC). However, the causal relationship between blood metabolites and BC remains unclear. METHOD: Comprehensive two-sample Mendelian randomization analysis was conducted to determine the causal association between 1400 publicly available genetic data on metabolic factors and human epidermal growth factor receptor positive (HER+) BC or HER- BC in this study. RESULT: Epiandrosterone sulfate levels (OR = 1.07, 95% CI = 1.02 ~ 1.10, p = 0.0013), 5alpha-androstan-3beta,17beta-diol monosulfate (2) levels (OR = 1.07, 95% CI = 1.03 ~ 1.12, p = 0.0012), glycohyocholate levels (OR = 0.85, 95% CI = 0.77 ~ 0.93, p = 0.0007) and etiocholanolone glucuronide levels (OR = 1.12, 95% CI = 1.05 ~ 1.20, p = 0.0013) were causally correlated with HER+ BC. 5 metabolites were causally correlated with HER- BC: Vanillic acid glycine levels (OR = 1.14, 95% CI = 1.06 ~ 1.22, p = 0.0003), Thyroxine levels (OR = 1.26, 95% CI = 1.11 ~ 1.44, p = 0.0004), 1-palmitoyl-2-linoleoyl-GPI (16:0/18:2) levels (OR = 0.86, 95% CI = 0.79 ~ 0.94, p = 0.0010), N-acetylphenylalanine levels (OR = 1.12, 95% CI = 1.05 ~ 1.19, p = 0.0007) and Glucose-to-mannose ratio (OR = 1.15, 95% CI = 1.06 ~ 1.24, p = 0.0008). Two common causally related metabolites were identified: Gamma-glutamyl glutamate and X-12849 levels. CONCLUSIONS: Our study has respectively demonstrated the connection between blood metabolites and HER+ or HER- BC by genetic means, thereby offering opportunities for therapeutic targets.

Integrated nomogram to predict HER2 expression in breast tumor: Clinical, Ultrasound, and Photoacoustic imaging approaches.

BACKGROUND: HER2 is a key biomarker for breast cancer treatment and prognosis. Traditional assessment methods like immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are effective but costly and time-consuming. Our model incorporates these methods alongside photoacoustic imaging to enhance diagnostic accuracy and provide more comprehensive clinical insights. MATERIALS AND METHODS: A total of 301 breast tumors were included in this study, divided into HER2-positive (3+ or 2+ with gene amplification) and HER2-negative (below 3+ and 2+ without gene amplification) groups. Samples were split into training and validation sets in a 7:3 ratio. Statistical analyses involved t-tests, chi-square tests, and rank-sum tests. Predictive factors were identified using univariate and multivariate logistic regression, leading to the creation of three models: ModA (clinical factors only), ModB (clinical plus ultrasound factors), and ModC (clinical, ultrasound, and photoacoustic imaging-derived oxygen saturation (SO2)). RESULTS: The area under the curve (AUC) for ModA was 0.756 (95 % CI: 0.69-0.82), ModB increased to 0.866 (95 % CI: 0.82-0.91), and ModC showed the highest performance with an AUC of 0.877 (95 % CI: 0.83-0.92). These results indicate that the comprehensive model combining clinical, ultrasound, and photoacoustic imaging data (ModC) performed best in predicting HER2 expression. CONCLUSION: The findings suggest that integrating clinical, ultrasound, and photoacoustic imaging data significantly enhances the accuracy of predicting HER2 expression. For personalised breast cancer treatment, the integrated model could provide a comprehensive and reproducible decision support tool.

Clinical Outcomes in Patients with Early Stage Node-Negative HER2-Positive Breast Cancer Receiving Upfront Surgery or Neoadjuvant Systemic Therapy.

BACKGROUND: HER2-positive breast cancer is traditionally treated with neoadjuvant systemic therapy (NST), but optimal treatment sequencing is less clear in patients with small tumors. We investigated clinicopathologic and oncologic outcomes in early stage HER2-positive breast cancer. PATIENTS AND METHODS: An institutional database was queried to identify patients with cT1-2 (≤ 3 cm) N0M0, HER2-positive breast cancer treated from 2015 to 2020 and compared upfront surgery and NST cohorts. Logistic regression was performed to identify factors predicting upstaging. Survival outcomes by group were compared using log-rank tests. RESULTS: Of 256 patients identified, 170 (66.4%) received upfront surgery and 86 (33.6%) NST. The NST cohort was younger and had more cT2 and grade 3 tumors and negative sentinel nodes. There was no significant difference in type of breast surgery or receipt of axillary lymphadenectomy. After upfront surgery, 4 (2.4%) patients had upstaging to pT > 3 cm and 18 (10.6%) to pN1-3. No factors predicted upstaging. After NST, 47 (54.7%) achieved pathologic complete response and 3 (3.5%) had upstaging to ypN1-3 with older age (OR 1.08, p = 0.004) and hormone receptor-positive status (OR 7.07, p = 0.002) identified as predictors. At median follow-up of 3.55 years, 10 (3.9%) patients had recurrence and 5 (2.0%) patients died. There were no significant differences in oncologic outcomes between groups. CONCLUSIONS: Patients with cT1-2 (≤ 3 cm)N0 HER2-positive breast cancer selected for NST have higher-risk disease. Low rates of pathologic upstaging were observed with no difference in surgical treatments and overall excellent oncologic outcomes in both groups. These findings may guide decision-making regarding treatment sequencing for patients with early stage HER2-positive disease.

Populations of triple negative and hormone receptor positive HER2 negative breast tumors share immune gene profiles.

In breast cancer, triple negative (TN) breast cancer has most responses to immune checkpoint inhibitor (ICI) therapy. Lymphocyte infiltrate does not impact prognosis in Hormone receptor positive HER2 negative (HR + HER2-) breast tumors and few HR + HER2- tumors respond to ICI. We contrasted immune-associated gene expression between 119 TN and 475 HR + HER2- breast tumors from The Cancer Genome Atlas (TCGA) and confirmed our findings in 299 TN and 1369 HR + HER2- breast tumors in the METABRIC database. TN and HR+ HER2- tumors grouped into immune-high or -low tumors, both subtypes were represented in the immune-high group. The largest difference between the immune-high TN and HR + HER2- tumors was TN tumors had more abundant Th1 and Th2 CD4+ T cells while HR + HER2- tumors had more abundant fibroblasts (log2FC > 0.3; p < 10×10-10). This suggests an immune-high signature is not dictated by breast cancer subtype, but fibroblast subsets associated with worse outcome were higher in the immune-high HR + HER2- tumors.

Management and Mechanisms of Diarrhea Induced by Tyrosine Kinase Inhibitors in Human Epidermal Growth Factor Receptor-2-Positive Breast Cancer.

Breast cancer has the highest incidence among female malignancies, significantly impacting women's health. Recently, numerous HER2-targeted therapies have achieved excellent clinical outcomes. Currently, anti-HER2 drugs are divided into three main categories: monoclonal antibodies, small-molecule tyrosine kinase inhibitors, and antibody-coupled drugs (ADCs). The main toxic side effects of small molecule TKI-based therapy are diarrhea, hand-foot syndrome, rash, nausea, and vomiting. Diarrhea is a potential predictor of tumor response, affecting up to 95% of cancer patients treated with TKIs. Severe gastrointestinal toxicity can result in the need for dose reductions and treatment interruptions. This not only compromises the efficacy of TKIs but also deteriorates human nutrition and quality of life. The majority of individuals develop diarrhea within 7 days of starting treatment, with approximately 30% developing grade 3 or higher diarrhea within 2-3 days of starting treatment. The severity of diarrhea typically correlates with the dosage of most TKIs. Current prevention and management strategies are primarily empirical, focusing on symptom alleviation rather than addressing the toxicological mechanisms underlying TKI-induced diarrhea. Consequently, anti-diarrheal drugs are often less effective in managing this condition in cancer patients receiving TKIs. Moreover, our understanding of the toxicological mechanisms responsible for such diarrhea remains limited, underscoring the urgent need to identify these mechanisms in order to develop effective anti-diarrheal medications tailored to this specific context. This review aims to elucidate management approaches and mechanisms for diarrhea induced by TKIs during HER2-positive breast cance.

Breast cancer has the highest incidence among female malignancies, significantly impacting women's health. In recent years, numerous HER2-targeted therapies have been developed, including lapatinib, neratinib, tucatinib, and pyrotinib. However, second-generation tyrosine kinase inhibitors (TKIs) often cause severe gastrointestinal toxicity, necessitating dose reduction and treatment interruption. This not only compromises the efficacy of TKIs but also deteriorates nutritional status and quality of life. Diarrhea is a potential predictor of tumor response and is the second most common adverse event, affecting up to 95% of cancer patients treated with TKIs. Approximately 30% of these patients experience grade 3 or higher diarrhea within just 2-3 days of initiating TKI treatment. The severity of diarrhea typically correlates with the dosage of most TKIs. Current prevention and management strategies are primarily empirical, focusing on symptom alleviation rather than addressing the toxicological mechanisms underlying TKI-induced diarrhea. Consequently, anti-diarrheal drugs are often less effective in managing this condition in cancer patients receiving TKIs. Moreover, our understanding of the toxicological mechanisms responsible for such diarrhea remains limited, underscoring the urgent need to identify these mechanisms to develop effective antidiarrheal medications tailored for this specific context. This review aims to elucidate management approaches for diarrhea induced by HER2 tyrosine kinase inhibitors during breast cancer treatment.

Weakly-supervised deep learning models enable HER2-low prediction from H &E stained slides.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-low breast cancer has emerged as a new subtype of tumor, for which novel antibody-drug conjugates have shown beneficial effects. Assessment of HER2 requires several immunohistochemistry tests with an additional in situ hybridization test if a case is classified as HER2 2+. Therefore, novel cost-effective methods to speed up the HER2 assessment are highly desirable. METHODS: We used a self-supervised attention-based weakly supervised method to predict HER2-low directly from 1437 histopathological images from 1351 breast cancer patients. We built six distinct models to explore the ability of classifiers to distinguish between the HER2-negative, HER2-low, and HER2-high classes in different scenarios. The attention-based model was used to comprehend the decision-making process aimed at relevant tissue regions. RESULTS: Our results indicate that the effectiveness of classification models hinges on the consistency and dependability of assay-based tests for HER2, as the outcomes from these tests are utilized as the baseline truth for training our models. Through the use of explainable AI, we reveal histologic patterns associated with the HER2 subtypes. CONCLUSION: Our findings offer a demonstration of how deep learning technologies can be applied to identify HER2 subgroup statuses, potentially enriching the toolkit available for clinical decision-making in oncology.

Radiologic-Pathologic Correlation: Is There an Association Between Contrast-Enhanced Mammography Imaging Features and Molecular Subtypes of Breast Cancer?

OBJECTIVE: This study aims to assess the correlation between imaging features of contrast-enhanced mammography (CEM) and molecular subtypes of breast cancer. METHODS: This is a retrospective single-institution study of patients who underwent CEM from December 2019 to August 2023. Each patient had at least one histologically proven invasive breast cancer with a core biopsy performed. Patients with a history of breast cancer treatment and lesions not entirely included in the CEM images were excluded. The images were interpreted using the American College of Radiology Breast Imaging Reporting and Data System (ACR BI-RADS) lexicon for CEM, published in 2022. Different imaging features, including the presence of calcifications, architectural distortion, non-mass enhancement, mass morphology, internal enhancement pattern, the extent of enhancement, and lesion conspicuity, were analyzed. The molecular subtypes were studied as dichotomous variables, including luminal A, luminal B, HER2, and basal-like. The association between the imaging features and molecular subtypes was analyzed with a Fisher's exact test. Statistical significance was assumed when the p-value was <0.05. RESULTS: A total of 31 patients with 36 malignant lesions were included in this study. Sixteen lesions (44.4%) were luminal A, four lesions (11.1%) were luminal B, 10 lesions (27.8%) were HER2, and six (16.7%) were basal-like subtypes. The presence of calcifications was associated with the HER2 subtype (p=0.024). Rim-enhancement on recombined images was associated with a basal-like subtype (p=0.001). Heterogeneous enhancement on recombined images was associated with non-basal-like breast cancer (p=0.027). No statistically significant correlation was found between other analyzed CEM imaging features and molecular subtypes. CONCLUSION: CEM imaging features, including the presence of calcifications and certain internal enhancement patterns, were correlated with distinguishing breast cancer molecular subtypes and thus may further expand the role of CEM.

Salivary duct carcinoma in the submandibular gland: A rare case report with differential diagnosis.

Salivary duct carcinoma (SDC) is a rare and highly aggressive malignant salivary gland neoplasm, accounting for only 0.2% of salivary gland tumours. It predominantly affects the parotid gland and represents a significant concern with limited prevalence (1-1.2 individuals per million). We present a case of a 65-year-old female patient with a clinical history of swelling and pain in the right lower jaw region for six months. Diagnostic investigations revealed a well-defined submandibular gland lesion. Subsequent histopathological and immunohistochemical findings confirmed the lesion to be SDC. This case report emphasises the challenges in diagnosing this aggressive malignancy, which stems from its rarity and resemblance to other neoplasms. It is worth noting that the involvement of the submandibular gland is observed in a mere 12% of SDC cases, while females account for only 25% of the reported instances.

Characteristics of sphingomyelin metabolism in the MCF7 and BT474 radiotherapy­resistant HER2­positive breast cancer cell lines.

Breast cancer is the most common cancer globally in terms of incidence. This cancer is classified into subtypes based on histological or immunological characteristics. HER2-positive cases account for 15-25% of breast cancer cases, and one of the first events in breast carcinogenesis is HER2 upregulation. Furthermore, HER2 expression increases the detection rate of metastatic or recurrent breast cancers by 50-80%. The epidermal growth factor receptor family includes HER2, which is a transmembrane receptor protein. In our previous case report, patients who were resistant to anti-HER2 monoclonal antibody therapy, chemotherapy and radiotherapy had higher concentrations of phospholipid metabolites such as phosphatidylcholine and sphingomyelin (SM), which was associated with cancer recurrence progression. To better understand the relationship between radiotherapy resistance and SM expression, breast cancer cell lines with and without HER2 expression (MCF7 and BT474) after exposure to ionizing radiation (IR) were examined. In the cell culture supernatant, similar levels of SM in MCF7 cells were identified after 1-4 Gy exposure. However, SM levels in BT474 cells were upregulated compared with those of in the control group. Intracellular SM levels were upregulated in BT474 cells exposed to 1 and 4 Gy compared with the non-irradiated control group. Furthermore, significantly increased mRNA expression levels of sphingomyelin synthase 2 (SGMS2) in BT474 cells exposed to IR were observed compared with those in nonirradiated cells; however, the SGMS2 levels in MCF7 cells did not differ significantly among the 0, 2 and 4 Gy groups. These findings suggested that a higher dose of IR induced the secretion of SM and its associated gene expression in HER2-positive breast cancer cells.

Neoadjuvant Therapy: Current Landscape and Future Horizons for ER-Positive/HER2-Negative and Triple-Negative Early Breast Cancer.

OPINION STATEMENT: Navigating the complex landscape of breast cancer treatment involves distinct strategies for luminal and triple-negative subtypes. While neoadjuvant chemotherapy historically dominates the approach for aggressive triple-negative tumors, recent evidence highlights the transformative impact of immunotherapy, alongside chemotherapy, in reshaping treatment paradigms. In luminal cancers, endocrine therapy, notably aromatase inhibitors, demonstrates promising outcomes in postmenopausal patients with low-grade luminal A tumors. However, integrating targeted therapies like CDK4/6 inhibitors in neoadjuvant setting remains inconclusive. Identifying predictive factors for treatment response, especially in luminal tumors, poses a challenge, emphasizing the necessity for ongoing research. A multidisciplinary approach, tailored to individual patient profiles, is crucial for maximizing efficacy while minimizing toxicity. As we strive to optimize breast cancer management, a comprehensive understanding of the distinct characteristics and treatment implications of luminal and triple-negative subtypes, including the transformative role of immunotherapy, is essential for informed decision-making and personalized care.

Clinicopathological and prognostic features of HER2-null and HER2-low advanced breast cancer treated with eribulin or capecitabine.

BACKGROUND: HER2-low populations constitute a heterogeneous group, and the cytotoxic anticancer agent efficacy based on HER2 status remains unclear. This study evaluated the clinicopathological features and outcomes of patients with advanced breast cancer showing HER2-low expression treated with eribulin or capecitabine, two treatment options after anthracycline and taxane treatment. METHODS: We retrospectively evaluated patients who were treated with eribulin or capecitabine between 2011 and 2015. HER2 status was evaluated according to the ASCO/CAP guidelines. RESULTS: No significant difference was observed in overall survival (OS; eribulin: hazard ratio [HR], 0.66; 95% CI 0.40-1.10; capecitabine: HR, 0.76; 95% CI 0.45-1.30) or progression-free survival (PFS; eribulin: HR, 1.13; 95% CI 0.72-1.78; capecitabine: HR, 0.90; 95% CI 0.56-1.44) between patients receiving eribulin (HER2-null: 35, HER2-low: 44) and those receiving capecitabine (HER2-null: 41, HER2-low: 33). Subgroup analysis revealed no significant differences in OS between the two groups in the hormone-positive and -negative populations for eribulin and capecitabine. HER2-null and HER2-low patients showed objective response rates (ORRs) of 22.5% and 9.1% (p = 0.09) overall, and 32.0% and 10.5% (p = 0.03), respectively, in hormone-positive cases among eribulin-treated patients. No response was observed in hormone-negative patients. Capecitabine treatment in HER2-null and HER2-low patients had overall ORRs of 26.8% and 15.2% (p = 0.23), respectively, with 27.3% and 16.1% (p = 0.28) for hormone-positive cases; and 25.0% and 0% (p = 1.0), respectively, for hormone-negative cases. CONCLUSIONS: Eribulin and capecitabine sensitivity may vary based on HER2 expression in patients with HER2-low and HER2-null breast cancer. Prognosis was similar between the HER2-low and the HER2-null groups.

The longitudinal changes in multiparametric MRI during neoadjuvant chemotherapy can predict treatment response early in patients with HER2-positive breast cancer.

PURPOSE: To investigate whether longitudinal changes in multiparametric MRI can predict early response to neoadjuvant chemotherapy (NAC) for HER2-positive breast cancer (BC) and to further establish quantitative models based on these features. METHODS: A total of 164 HER2-positive BC patients from three centers were included. MRI was performed at baseline and after two cycles of NAC (early post-NAC). Clinicopathological characteristics were enrolled. MRI features were evaluated at baseline and early post-NAC, as well as longitudinal changes in multiparametric MRI, including changes in the largest diameter (LD) of the tumor (ΔLD), apparent diffusion coefficient (ADC) values (ΔADC), and time-signal intensity curve (TIC) (ΔTIC). The patients were divided into a training set (n = 95), an internal validation set (n = 31), and an independent external validation set (n = 38). Univariate and multivariate logistic regression analyses were used to identify the independent indicators of pCR, which were then used to establish the clinicopathologic model and combined model. The AUC was used to evaluate the predictive power of the different models and calibration curves were used to evaluate the consistency of the prediction of pCR in different models. Additionally, decision curve analysis (DCA) was employed to determine the clinical usefulness of the different models. RESULTS: Two models were enrolled in this study, including the clinicopathologic model and the combined model. The LD at early post-NAC (OR=0.913, 95 % CI=0.953-0.994 p = 0.026), ΔADC (OR=1.005, 95 % CI=1.005-1.008, p = 0.007), and ΔTIC (OR=3.974, 95 % CI=1.276-12.358, p = 0.017) were identified as the best predictors of NAC response. The combined model constructed by the combination of LD at early post-NAC, ΔADC, and ΔTIC showed good predictive performance in the training set (AUC=0.87), internal validation set (AUC=0.78), and external validation set (AUC=0.79), which performed better than the clinicopathologic model in all sets. CONCLUSIONS: The changes in multiparametric MRI can predict early treatment response for HER2-positive BC and may be helpful for individualized treatment planning.

Na+/H+-exchange inhibition by cariporide is compensated via Na+,HCO3--cotransport and has no net growth consequences for ErbB2-driven breast carcinomas.

Defense against intracellular acidification of breast cancer tissue depends on net acid extrusion via Na+,HCO3--cotransporter NBCn1/Slc4a7 and Na+/H+-exchanger NHE1/Slc9a1. NBCn1 is increasingly recognized as breast cancer susceptibility protein and promising therapeutic target, whereas evidence for targeting NHE1 is discordant. Currently, selective small molecule inhibitors exist against NHE1 but not NBCn1. Cellular assays-with some discrepancies-link NHE1 activity to proliferation, migration, and invasion; and disrupted NHE1 expression can reduce triple-negative breast cancer growth. Studies on human breast cancer tissue associate high NHE1 expression with reduced metastasis and-in some molecular subtypes-improved patient survival. Here, we evaluate Na+/H+-exchange and therapeutic potential of the NHE1 inhibitor cariporide/HOE-642 in murine ErbB2-driven breast cancer. Ex vivo, cariporide inhibits net acid extrusion in breast cancer tissue (IC50 = 0.18 µM) and causes small decreases in steady-state intracellular pH (pHi). In vivo, we deliver cariporide orally, by osmotic minipumps, and by intra- and peritumoral injections to address the low oral bioavailability and fast metabolism. Prolonged cariporide administration in vivo upregulates NBCn1 expression, shifts pHi regulation towards CO2/HCO3--dependent mechanisms, and shows no net effect on the growth rate of ErbB2-driven primary breast carcinomas. Cariporide also does not influence proliferation markers in breast cancer tissue. Oral, but not parenteral, cariporide elevates serum glucose by ∼1.5 mM. In conclusion, acute administration of cariporide ex vivo powerfully inhibits net acid extrusion from breast cancer tissue but lowers steady-state pHi minimally. Prolonged cariporide administration in vivo is compensated via NBCn1 and we observe no discernible effect on growth of ErbB2-driven breast carcinomas.

Prognostic factors of patients with human epidermal growth factor receptor 2-positive breast cancer following neoadjuvant therapy: Development and validation of a predictive nomogram.

OBJECTIVE: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer exhibits an aggressive phenotype and poor prognosis. The application of neoadjuvant therapy (NAT) in patients with breast cancer can significantly reduce the risks of disease recurrence and improve survival. By integrating different clinicopathological factors, nomograms are valuable tools for prognosis prediction. This study aimed to assess the prognostic value of clinicopathological factors in patients with HER2-positive breast cancer and construct a nomogram for outcome prediction. METHODS: We retrospectively analyzed the clinicopathological data from 374 patients with breast cancer admitted to the Fourth Hospital of Hebei Medical University between January 2009 and December 2017, who were diagnosed with invasive breast cancer through preoperative core needle biopsy pathology, underwent surgical resection after NAT, and were HER2-positive. Patients were randomly divided into a training and validation set at a ratio of 7:3. Univariate and multivariate survival analyses were performed using Kaplan-Meier and Cox proportional hazards regression models. Results of the multivariate analysis were used to create nomograms predicting 3-, 5-, and 8-year overall survival (OS) rates. Calibration curves were plotted to test concordance between the predicted and actual risks. Harrell C-index and time-dependent receiver operating characteristic (ROC) curves were used to evaluate the discriminability of the nomogram prediction model. RESULTS: All included patients were women, with a mean age of 50 ± 10.4 years (range: 26-72 years). In the training set, both univariate and multivariate analyses identified residual cancer burden (RCB) class, tumor-infiltrating lymphocytes(TILs), and clinical stage as independent prognostic factors for OS, and these factors were combined to construct a nomogram. The calibration curves demonstrated good concordance between the predicted and actual risks, and the C-index of the nomogram was 0.882 (95 % CI 0.863-0.901). The 3-, 5-, and 8-year areas under the ROC curve (AUCs) were 0.909, 0.893, and 0.918, respectively, indicating good accuracy of the nomogram. The calibration curves also demonstrated good concordance in the validation set, with a C-index of 0.850 (95 % CI 0.804-0.896) and 3-, 5-, and 8-year AUCs of 0.909, 0.815, and 0.834, respectively, which also indicated good accuracy. CONCLUSION: The nomogram prediction model accurately predicted the prognostic status of post-NAT patients with breast cancer and was more accurate than clinical stage and RCB class. Therefore, it can serve as a reliable guide for selecting clinical treatment measures for breast cancer.

Tumor immune microenvironmental characteristics in Human Epidermal Growth Factor-2 (HER2) positive esophageal adenocarcinoma: A comparative analysis and biomarker study.

BACKGROUND: HER2 targeting in esophageal adenocarcinoma (EAC) has shown potential, but often fails to show durable response. Given the contributions of the tumor immune microenvironment (TIME) to therapeutic responses, we aimed to chart the TIME characteristics of HER2 positive tumors. METHODS: 84 biopsies were taken from the TRAP cohort (neoadjuvant chemoradiotherapy (nCRT) according to CROSS with trastuzumab and pertuzumab; n = 40; HER2+n = 40) and a control cohort with nCRT only (n = 44; HER2- n = 40, HER2+n = 4) before treatment. Biopsies were analysed using targeted gene expression analysis (Nanostring immune-oncology panel, 750 genes). Differential gene expression was assessed between HER2 positive (n = 44) vs. negative biopsies (n = 40), and non-responders (n = 17) vs. responders (n = 23) to anti-HER2 treatment. Statistical significance was determined as p-value <0.05, adjusted for multiple testing correction. RESULTS: 83 biopsies were eligible for analyses following quality control (TRAP cohort n = 40; control cohort n = 43); there were no significant differences in clinical characteristics between the TRAP vs. control the cohort or HER2 positive vs. HER2 negative biopsies. HER2 expression was found to associate with epithelial markers (EPCAM p < 0.001; E-cadherin p < 0.001). Moreover, HER2 expression was associated with a lower expression of immune cell infiltration, such as NK-cells (p < 0.001) and CD8 T-cells (p < 0.001), but also lower expression of immune exhaustion markers (PDCD1LG2, CTLA4; p < 0.001). In non-responders to anti-HER2 treatment, baseline biopsies showed increased expression of immune exhaustion markers, as well as hypoxia and VEGF signalling. DISCUSSION: HER2 expression was associated with epithelial tumor characteristics. The HER2 positive TIME showed reduced immune cell infiltration but also lower expression of inhibitory signals associated with immune exhaustion, questioning the mechanism behind potential clinical benefit of co-administration of anti-HER2 agents and checkpoint inhibitors. As limited response was associated with increased VEGF signalling, studies could investigate potential synergism of targeting VEGF and HER2.

Optimal systemic treatment and real-world clinical application of ctDNA in patients with metastatic HER2-mutant lung cancer.

INTRODUCTION: No definitive answers currently exist regarding optimal first-line therapy for HER2-mutant NSCLC. Access to rapid tissue sequencing is a major barrier to precision drug development in the first-line setting. ctDNA analysis has the potential to overcome these obstacles and guide treatment. METHODS: We retrospectively analyzed patients with metastatic HER2-mutant NSCLC who underwent prospective clinical ctDNA sequencing and received systemic therapy at Memorial Sloan Kettering Cancer Center (MSK) from January 2016 to September 2022. HER2 mutations were identified by next-generation sequencing through MSK-IMPACT, MSK-ACCESS or Resolution ctDx LungTM assay. Primary endpoints were time to the next treatment (TTNT) and overall survival (OS). RESULTS: Sixty-three patients were included in the primary analysis. Chemoimmunotherapy (33/63, 52.4 %) was the predominant first-line treatment with a median TTNT of 5.1 months (95 %CI 4.1 - 6.1) whereas 55.0 % (22/40) of patients who received second-line T-DXd obtained a median TTNT of 9.2 m (95 % CI, 0-22.2). Plasma ctDNA was tested before first-line therapy in 40 patients with a median OS of 28.0 months (95 % CI 21-34), in whom 31 patients (78.0 %) had detectable ctDNA. HER2 mutations were detected on ctDNA with a median turnaround time of 13 days, occasionally co-occurred with EGFR and MET alterations and were tracked longitudinally correlating with treatment response. Patients with detectable baseline ctDNA had significantly shorter OS (hazard ratio (HR), 5.25; 95 % CI, 1.2-23.9; p = 0.019). CONCLUSION: Chemoimmunotherapy remains a major treatment option for metastatic HER2-mutant NSCLC. ctDNA can rapidly detect HER2 and co-mutations, and it has the potential to guide and monitor optimal first-line therapy. As a negative prognostic biomarker, detectable ctDNA at baseline would need to be taken into account for patient selection in future studies.

Hierarchical Bifunctional NiO Electrocatalyst: Highly Porous Structure Boosting the Water Splitting Activity.

The development of an efficient, low-cost and earth-abundant electrocatalyst for water splitting is crucial for the production of sustainable hydrogen energy. However their practical applications are largely restricted by their limited synthesis methods, large overpotential and low surface area. Hierarchical materials with a highly porous three-dimensional nanostructure have garnered significant attention due to their exceptional electrocatalytic properties. These hierarchical porous frameworks enable the fast electron transfer, rapid mass transport, and high density of unsaturated metal sites and maximize product selectivity. Here the process involved obtaining monodispersed microrod-shaped Ni(OH)2 through a hydrothermal reaction, followed by a heat treatment to convert it into hierarchical microrod-shaped NiO materials. N2 sorption analysis revealed that the BET surface area increased from 9 to 89 m2/g as a result of the heat treatment. The hierarchical microrod-shaped NiO materials demonstrated outstanding bifunctional electrocatalytic water splitting capabilities, excelling in both HER and OER in basic solution. Overpotential of 347 mV is achieved at 10 mA/cm2 for OER activity, with a Tafel slope of 77 mV/dec. Similarly, overpotential of 488 mV is achieved at 10 mA/cm2 for HER activity, with a Tafel slope of 62 mV/dec.

Unveiling Neoadjuvant Therapy: Insights and Outlooks for HER2-Positive Early Breast Cancer.

OPINION STATEMENT: This perspective underscores the evolution and significance of neoadjuvant therapy in breast cancer, tracing its history and efficacy in improving outcomes. It delves into the correlation between achieving complete response and long-term survival, emphasizing the predictive value of treatment response estimation. Neoadjuvant chemotherapy in HER2-positive early breast cancer, particularly with taxanes and anti-HER2 therapies, emerges as a cornerstone, offering enhanced breast conservation rates and prognostic insights. The focus on individualized care, tailored to treatment response, underscores the need for adaptive strategies. Additionally, the article discusses the ongoing debate surrounding anthracyclines' role and the benefits of dual HER2 blockade. Ultimately, advocating for a personalized approach, guided by treatment response assessment, ensures optimal outcomes in HER2-positive breast cancer management.