595 Background: Neoadjuvant de-escalation chemo-immunotherapy with abbreviated cycles remains unclear. We aimed to assess the efficacy and safety of toripalimab, a novel PD-1 antibody, combined with an abbreviated course of epirubicin–cyclophosphamide (2 cycles) followed by nab-paclitaxel (2 cycles), as a neoadjuvant regimen for early-stage TNBC patients. Methods: This phase II trial, conducted from 2024 to 2025, involved stage II–III TNBC. The neoadjuvant regimen included epirubicin, cyclophosphamide, and toripalimab for 2 cycles, followed by nab-paclitaxel and toripalimab for another 2 cycles. Patients achieving a pathological complete response (pCR) received up to 13 cycles of adjuvant toripalimab, while those with residual disease received additional chemotherapy and toripalimab. Whole-exome sequencing (WES) and circulating tumor DNA (ctDNA) monitoring were also performed. The primary endpoint was the total pCR (tpCR) rate (ypT0/is ypN0). Secondary endpoints included breast pCR (bpCR; ypT0/is), residual cancer burden (RCB 0–1), objective response rate (ORR), and event-free survival. This trial was registered with ClinicalTrials.gov (NCT06682195). Results: As of January 20, 2026, 48 patients were enrolled, and 40 underwent surgery (median age: 48 years; 87.5% stage II). WES analysis in 37 patients identified BRCA1 mutations in 12 (32.4%). Baseline ctDNA was positive in 32 of 34 (94.1%) patients, and 24 (75%) achieved ctDNA negativity after neoadjuvant therapy. Among 40 surgical patients, tpCR, bpCR, RCB 0-I, and ORR rates were 55%, 60%, 70, and 92.5%, respectively. Subgroup analyses showed tpCR rates of 25% for CPS <1, 58.3% for CPS ≥1, 72.7% for CPS ≥10, and 80% for CPS ≥20. For TILs <10, tpCR was 25%, increasing to 66.6% for TILs ≥10, 82.3% for TILs ≥30, and 85.7% for TILs ≥50. Among BRCA1 mutation carriers, 75% achieved tpCR, and 62.5% of patients with ctDNA negativity also achieved tpCR. Grade ≥3 AEs occurred in 6 (15%) patients, most commonly vomiting (7.5%) and leukopenia (7.5%). Hypothyroidism was the most frequent immune-related AE (17.5%, all grade 1–2). Conclusions: Preliminary findings indicate that this 4 cycles de-escalation neoadjuvant strategy is effective and safe for early-stage TNBC, warranting further investigation in randomized trials. Clinical trial information: NCT06682195 . Response endpoints for the entire cohort (N = 40). Efficacy endpoint N (%) 95% CI(%) tpCR(ypT0/is, ypN0) 22(55.0) 38.5–70.4 bpCR(ypT0/is) 24(60.0) 43.3–75.0 Miller–Payne (MP) grades MP score 1 2 (5.0) 0.6-23.2 MP score 2 3 (7.5) 1.6-27.3 MP score 3 7 (17.5) 7.3-34.7 MP score 4 4 (10.0) 2.8-23.7 MP score 5 24 (60.0) 43.3.-75.0 Residual cancer burden (RCB) class RCB class 0–I 28(70.0) 53.3–83.4 RCB class II 6 (15.0) 5.7-31.9 RCB class III 6 (15.0) 5.7-31.9 Abbreviations: tpCR, total pathological complete response; bpCR, breast pathological complete response; CI, confidence interval.

AIM:This study aimed to investigate the causal associations between nine cathepsins (B, E, F, G, H, L2, O, S, Z) and breast carcinogenesis using Mendelian Randomization (MR) analysis, thereby addressing the current lack of systematic causal evidence beyond observational studies. METHODS:Genetic instruments for circulating cathepsin levels were obtained from the INTERVAL study, and summary statistics for breast cancer were derived from the TRICL consortium. Univariate MR with Inverse Variance Weighting (IVW) served as the primary analysis, supplemented by assessments of heterogeneity, pleiotropy, and outliers. Multivariable MR was performed to confirm independent associations, and reverse MR was used to explore potential feedback from breast cancer to cathepsin expression. RESULTS:Higher genetically predicted cathepsin E was causally associated with an increased risk of breast cancer, whereas cathepsins O and S were protective. No significant associations were observed for the other six cathepsins. Multivariable MR confirmed these associations as independent of one another. Reverse MR suggested that breast cancer liability downregulates cathepsin H but does not influence cathepsins E, O, or S. CONCLUSION:This is the first MR study to provide causal evidence implicating cathepsin E as a risk factor and cathepsins O and S as protective factors in breast cancer. The findings highlight the novelty of identifying specific cathepsins with opposing effects, nominating cathepsin E as a candidate serum biomarker and cathepsins O and S as potential therapeutic targets. These results warrant validation in diverse, multi-ethnic cohorts and longitudinal studies.

27 Background: Neoadjuvant docetaxel plus carboplatin with trastuzumab and pertuzumab (TCbHP) is the standard regimen for HER2-positive breast cancer, yet 22%–25% of patients develop resistance to monoclonal antibody–based anti-HER2 therapy. Inetetamab, an anti-HER2 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity, and pyrotinib, an oral irreversible pan-HER tyrosine kinase inhibitor targeting HER1/2/4, are effective in advanced HER2-positive breast cancer, but their combined neoadjuvant use remains underexplored. We conducted a prospective, single-arm trial (NCT06234137) to evaluate inetetamab, pyrotinib, and chemotherapy in HER2-positive locally advanced breast cancer with high tumor burden. Methods: Patients with non-metastatic, HER2-positive stage II–III primary breast cancer eligible for neoadjuvant therapy were enrolled. The primary endpoint was total pathological complete response (tpCR); secondary endpoints included objective response rate, safety, immunogenicity, and survival outcomes. Sample size was determined using Simon’s two-stage design (null tpCR 45% vs alternative 60%, one-sided α = 0.05, power = 90%). Neoadjuvant therapy comprised inetetamab (8 mg/kg loading then 6 mg/kg IV q3w ×6), pyrotinib (400 mg orally once daily for 18 weeks), and docetaxel (75 mg/m²) plus carboplatin (AUC 6) q3w ×6; treatment continued until completion, progression, or unacceptable toxicity, with surgery 2–4 weeks later and continuation of anti-HER2 therapy to complete one year. Results: Between December 2021 and October 2025, 124 patients were enrolled across seven centers, with 108 evaluable for efficacy. Total pathological complete response (tpCR; ypT0/is, ypN0) occurred in 65 patients (60.2%, 95% CI 50.8–69.6), while breast pathological complete response (bpCR; ypT0/is) was 65.7% (95% CI 56.6–74.8). The objective response rate was 92.6% (95% CI 87.6–97.6), and disease control rate was 100%. Hormone receptor (HR)–negative disease achieved higher tpCR and bpCR rates than HR-positive disease (tpCR: 73.3% vs 43.8%; bpCR: 76.7% vs 52.1%). Multivariate analysis identified HR status as an independent predictor of efficacy (p < 0.05); favorable responses were also associated with premenopausal status, smaller tumor size, earlier nodal stage, lower disease stage, higher Ki-67 index, and higher histological grade. Conclusions: Neoadjuvant inetetamab plus pyrotinib and chemotherapy may provide substantial benefit in HER2-positive locally advanced breast cancer, particularly in HR-negative disease and high proliferative features. Research Sponsor: Special Funding Project for Characteristic Directional S-Disciplines of the First Affiliated Hospital of Wenzhou Medical University (wyyy-2025S01). Clinical trial information: NCT06234137 .

BACKGROUND:Triple-negative breast cancer (TNBC) is characterized by its rapid progression and aggressive nature, with limited effective therapeutic interventions currently available. Cyclovirobuxine D (CVB-D), a natural alkaloid extracted from the traditional Chinese herb Buxus sinica, is renowned for its cardioprotective and anti-ischemic effects, demonstrating notable anti-cancer properties. Nevertheless, the anti-tumor effects of CVB-D on TNBC remain unverified. PURPOSE:This study seeks to investigate the effects of CVB-D on TNBC and to uncover the underlying mechanisms. STUDY DESIGN:Network pharmacology, SPR, DSF, and cell-based functional assays were conducted on TNBC cells to assess the impact of CVB-D. Findings were further corroborated using xenograft mouse models. METHODS:Cell Counting Kit-8, 5-Ethynyl-2'-deoxyuridine, transwell assays, flow cytometry, wound healing assays, immunofluorescence, and immunoblotting were employed to evaluate CVB-D's influence on TNBC cell lines. SPR, DSF and molecular docking techniques were utilized to assess the binding affinity of CVB-D to Yes-associated protein (YAP). The interaction between CVB-D and autophagy/mitophagy was further analyzed through plasmid transient transfection, JC-1 assay, TUNEL assay, and the use of autophagy inhibitors. The anti-TNBC mechanism of CVB-D was elucidated by overexpressing YAP in MDA-MB-231 cells. Additionally, the in vivo efficacy and safety of CVB-D were assessed in a xenograft mouse model. RESULTS:In vitro analyses revealed that CVB-D effectively suppressed G1 phase arrest and inhibited TNBC cell proliferation. Moreover, CVB-D induced mitochondrial-dependent apoptosis and reduced cell migration by antagonizing epithelial-mesenchymal transition. Mechanistically, CVB-D exerted its anti-cancer effects by directly binding to YAP, thereby inhibiting the nuclear translocation of YAP/TAZ and suppressing the transcription of downstream oncogenic target genes. Furthermore, CVB-D triggered excessive mitophagy by activating the FOXO3a/PINK1-Parkin axis, promoting apoptosis and leading to mitochondrial dysfunction in TNBC cells. Elevated YAP expression counteracted the effects of CVB-D on TNBC, including the suppression of mitophagy-related protein expression induced by CVB-D, suggesting that YAP modulates mitophagy through the FOXO3a/PINK1-Parkin axis. The anti-tumor efficacy of CVB-D and its underlying mechanisms were further substantiated using a subcutaneous xenograft model. CONCLUSIONS:This study is the first to demonstrate that CVB-D can directly bind to the YAP target, proposing a novel therapeutic strategy for TNBC. CVB-D may serve both as a YAP/TAZ inhibitor and as an activator of the FOXO3a/PINK1-Parkin axis, leading to excessive mitophagy.

Papillary thyroid carcinoma (PTC) is one of the most common endocrine malignancies, with varying levels of risk and clinical behavior. A better understanding of the molecular characteristics could improve molecular diagnosis and risk assessment. In this study, we performed whole transcriptomic sequencing on 113 PTC cases, including 70 high-risk and 43 low-risk Chinese patients. Comparative transcriptional profiling analysis revealed two functionally distinct patterns of gene dysregulation between the risk subtypes. Low-risk PTCs showed significant upregulation of immune-related genes and increased immune cell infiltration, whereas high-risk PTCs presented extensive alterations in gene expression and activation of oncogenic signaling pathways. Additionally, we developed a 31-gene transcriptomic signature (PTCrisk) for differentiating high-risk from low-risk PTCs, which was validated across both in-house and external multicenter cohorts. PTCrisk scores were positively correlated with key clinicopathological features, including tumor size, lymph node metastasis, TNM stage, and BRAF mutation status. Overall, our study provides further molecular insights into PTC risk stratification and may contribute to the development of personalized therapeutic strategies for PTC patients.

BACKGROUND:Breast cancer ranks first in the global incidence rate of cancer among women. Triple-negative breast cancer (TNBC) is considered to be the most dangerous type because of the lack of specific therapeutic targets and rapid progression. The emergence of ferroptosis provides a new therapeutic perspective for TNBC. α-Hederin is a triterpenoid saponin derived from the traditional Chinese medicine Ivy, which has been proven to have anti-cancer effects on various cancers, but its efficacy and mechanism of inducing ferroptosis in TNBC remain to be further clarified. OBJECT:To investigate the effect and mechanism of α-Hederin induced ferroptosis in TNBC. METHOD:Cell viability was measured by CCK-8 assay, and cell proliferation and migration were evaluated by clone assay and scratch assay. The effect of α-Hederin on TNBC cell apoptosis was assessed by flow cytometry. Transcriptomics searches for critical pathways. Intracellular and lipid reactive oxygen species and Fe2+and Fe were detected by DCFH-DA probe, FerroOrange fluorescent probe and C11-BODIPY fluorescent probe, and the contents of malondialdehyde and reduced glutathione were detected by MDA and GSH kits. Erastin was used as a positive control for ferroptosis and Ferrrostatin-1(Fer-1) as an inhibitor. The relationship between α-Hederin and GPX4, IRF was analyzed by western blot and si-RNA, and the association was further confirmed by molecular simulation docking, external SPR experiments, and luciferase experiments. Constructing xenograft mouse models and human derived organoid models to evaluate the anti-TNBC efficacy of α-Hederin, and verifying the efficacy and ferroptosis mechanism of the drug in vivo through HE staining and IHC. RESULT:α-Hederin significantly inhibited the progression of TNBC. In vitro, α-Hederin decreased cancer cell viability through ferroptosis, increased glutathione degradation and MDA production, and promoted intracellular Fe2+ and ROS production, whereas Fer-1, an ferroptosis inhibitor, reversed this effect. Mechanistically, molecular docking and SPR experiments showed binding of α-Hederin to the key regulator IRF1, and knockdown/overexpression of IRF1 significantly affected the expression of GPX4, a downstream target of the ferroptosis pathway. In vivo, α-Hederin prevented tumor growth in xenograft and organoid models via the IRF1/GPX4 axis. CONCLUSION:We proved for the first time in this research that α-Hederin exerts anti-TNBC effects through a novel IRF1/GPX4 ferroptosis pathway.

BACKGROUND:The TCbHP regimen, consisting of combining docetaxel (T), carboplatin (Cb), trastuzumab (H), and pertuzumab (P), is the preferred neoadjuvant treatment for locally advanced human epidermal growth factor 2 (HER2)-positive breast cancer. However, about 40 % of patients develop resistance to this treatment. Adding TKIs like pyrotinib to anti-HER2 antibodies may enhance efficacy and reduce resistance, but the mechanisms are not fully understood. METHODS:Imaging mass cytometry (IMC) analyzed tissues from 26 patients treated with NeoPICD (docetaxel, carboplatin, pyrotinib, inetetamab) and 21 patients treated with TCbHP. Cellular changes and spatial relationships were assessed pre- and post-treatment. A co-culture system of tumor cells, fibroblasts, and PBMCs were used to examined cytotoxic T-cell function. A predictive model for treatment outcomes was constructed based on these results. RESULTS:In TCbHP-sensitive patients, IDOhiHLA-DRhi epithelial cells expressing PD-L1 were enriched and interacted with Ki67+ T cells and M1 macrophages. In TCbHP-resistant patients, fibroblasts formed a barrier that hindered immune cell access, critical for resistance. NeoPICD disrupted this barrier, enhancing immune cell infiltration and alleviating resistance. Machine learning based on spatial cell architecture can predict treatment outcomes. CONCLUSION:Spatial organization of cellular interactions in the tumor microenvironment (TME) provides insights into prognosis beyond pathological subtypes. The role of NeoPICD in disruption of fibroblast barriers and enhancement of immune cell function suggests therapeutic advantages in overcoming resistance to anti-HER2 therapies. This research offers new strategies for precision treatment of locally advanced HER2-positive breast cancer.

Background: Approximately one-third of patients with HER2-positive breast cancer experienced recurrence within 10 years after receiving 1 year of adjuvant trastuzumab. The ExteNET study showed that 1 year of extended adjuvant neratinib after trastuzumab-based adjuvant therapy could reduce invasive disease-free survival (iDFS) events compared with placebo. This study investigated the efficacy and safety of pyrotinib, an irreversible pan-HER receptor tyrosine kinase inhibitor, after trastuzumab-based adjuvant therapy in patients with high-risk, HER2-positive early or locally advanced breast cancer. Methods: This multicenter phase II trial was conducted at 23 centers in China. After enrollment, patients received 1 year of extended adjuvant pyrotinib (400 mg/day), which should be initiated within 6 months after the completion of 1-year adjuvant therapy (trastuzumab alone or plus pertuzumab). The primary endpoint was 2-year iDFS rate. Results: Between January 2019 and February 2022, 141 eligible women were enrolled and treated. As of October 10, 2022, the median follow-up was 24 (interquartile range, 18.0–34.0) months. The 2-year iDFS rate was 94.59% (95% confidence interval [CI]: 88.97–97.38) in all patients, 94.90% (95% CI: 86.97–98.06) in patients who completed 1-year treatment, 90.32% (95% CI: 72.93–96.77) in patients who completed only 6-month treatment, 96.74% (95% CI: 87.57–99.18) in the hormone receptor (HR)-positive subgroup, 92.77% (95% CI: 83.48–96.93) in the HR-negative subgroup, 96.88% (95% CI: 79.82–99.55) in the lymph node-negative subgroup, 93.85% (95% CI: 86.81–97.20) in the lymph node-positive subgroup, 97.30% (95% CI: 82.32–99.61) in patients with adjuvant trastuzumab plus pertuzumab, and 93.48% (95% CI: 86.06–97.02) in patients with adjuvant trastuzumab. The most common adverse events were diarrhea (79.4%), fatigue (36.9%), lymphocyte count decreased (36.9%), nausea (33.3%), and hand-foot syndrome (33.3%). Conclusions: Extended adjuvant pyrotinib administrated after trastuzumab-based adjuvant therapy showed promising efficacy in patients with high-risk HER2-positive breast cancer. The follow-up is ongoing to determine the long-term benefit. Funding: No external funding was received for this work. Clinical trial number: ClinicalTrials.gov: NCT05880927

Background: Ongoing discussions persist concerning the precedence of neoadjuvant therapy (NAT) relative to adjuvant therapy (AT) for patients with T1c, node-negative, triple-negative breast cancer (TNBC), and pertinent guidelines for these individuals are absent. Methods: Women diagnosed with T1cN0M0-stage TNBC who received chemotherapy and surgery were selected from the Surveillance, Epidemiology and End Results database (2010-2020). To balance baseline characteristics and mitigate selection bias, propensity score matching (PSM) was used to create the NAT and AT cohorts. Kaplan-Meier (KM) analysis and Cox proportional hazards models were performed to assess the prognostic factors for overall survival (OS) and breast cancer-specific survival (BCSS). Logistic regression models were utilized to identify predictive factors for response to NAT. Results: A total of 1033 patient pairs passed the PSM process, resulting in a well-balanced distribution. The KM analysis demonstrated that patients who received AT and those who underwent NAT had similar OS and BCSS, no matter before or after PSM. The multivariate Cox model showed that not achieving pathological complete response (non-pCR) following NAT, compared to AT, was associated with considerably worse OS (hazard ratio [HR], 2.207; 95 % confident intervaI [CI], 1.431-3.405; p < 0.001) and worse BCSS (HR, 2.184; 95 % CI, 1.348-3.537; p = 0.002). The logistic regression model revealed that being under 50 years old and having grade III or undifferentiated disease were independent predictors of pCR. Conclusions: In patients with T1cN0M0-stage TNBC, both NAT and AT resulted in equivalent OS and BCSS. However, NAT precisely helped select patients with worse prognosis.

Phosphodiesterase 4D interacting protein (PDE4DIP) is a Golgi/centrosome-associated protein that plays critical roles in the regulation of microtubule dynamics and maintenance of the Golgi structure. However, its biological role in human cancer remains largely unknown. In this study, we showed that PDE4DIP is overexpressed in human non-small cell lung cancer (NSCLC) tissues and that upregulated PDE4DIP expression is associated with poor prognosis in patients with lung cancer. We demonstrated that PDE4DIP knockdown inhibits NSCLC cell proliferation in vitro and tumorigenicity in vivo. We further demonstrated that PDE4DIP knockdown triggers apoptosis and cell cycle arrest in NSCLC cells by activating the Protein kinase A (PKA) /CREB signalling pathway. PDE4DIP coordinates with A-kinase anchoring proteins 9 (AKAP9) to enhance the Golgi localization and stability of PKA RIIα. Depletion of PDE4DIP mislocalizes PKA RIIα from the Golgi and leads to its degradation, thereby compromising its negative regulatory effect on PKA signalling. Overall, our findings provide novel insights into the roles of the PDE4DIP-AKAP9 complex in regulating PKA signalling and NSCLC growth and highlight PDE4DIP as a promising therapeutic target for NSCLC. Mechanistic exploration of PDE4DIP in the progression of non-small cell lung cancer (NSCLC) demonstrates that PDE4DIP coordinates with AKAP9 to promotes NSCLC growth via regulating PKA/CREB signaling pathway.

ABSTRACT Breast cancer is a highly heterogeneous malignancy among women worldwide. Traditional prognostic models relying solely on clinicopathological features offer limited predictive accuracy and lack molecular‐level insights. Unlike such conventional approaches, this study integrates proteomic and clinical data within an interpretable deep learning framework to improve prognostic precision and biological interpretability. We aimed to develop a more reliable model to accurately predict the 5‐year survival status of patients with breast cancer using multi‐omics data. The model integrating proteomics and clinical features demonstrated superior performance (AUC = 0.8136) compared to other feature combination models. The optimized model with 13 key features (4 clinical features and 9 proteins) achieved an AUC of 0.864 with the precision of 0.970, the recall of 0.810, and F1‐score of 0.883. SHapley Additive exPlanations analysis identified MPHOSPH10, EGFR, ARL3, KRT18, lymph node status, and HER2 status as the most influential features, while Kolmogorov–Arnold Network analysis provided explicit mathematical relationships between key contributors and prediction outcomes. Collectively, our interpretable multi‐modal model demonstrates robust performance in predicting 5‐year survival in breast cancer patients and offers mechanistic insights, thereby enhancing its potential for clinical translation through the development of an accessible prediction tool.

[This corrects the article on p. 1453 in vol. 11, PMID: 31938243.].

Objectives: Invasive micropapillary carcinoma (IMPC) stands out as a distinct and notably aggressive variant of breast cancer, and is known for its propensity for spreading to regional lymph nodes. The variability in the number of lymph nodes removed during surgery complicates assessment of the metastatic risk, an issue that is even more pronounced in IMPC due to its tendency for lymphatic spread. In this study, we evaluated the role of the lymph node ratio (LNR) in forecasting the outcomes of IMPC and developed a predictive nomogram for breast cancer-specific survival (BCSS) in patients with IMPC. Methods: We analyzed data from 1,697 female patients diagnosed with IMPC, gathered from the Surveillance, Epidemiology, and End Results (SEER) database spanning 2010 to 2020. Participants were randomly assigned to either a training set or an internal validation set in a 7:3 ratio. An additional group of 176 patients from our institution was an external validation cohort (SZSPH cohort). Key prognostic indicators were identified by univariate analyses and the least absolute shrinkage and selection operator (LASSO) regression technique. Then we crafted a novel nomogram that integrates all independent prognostic indicators and a thorough validation of the nomogram's predictive capability was conducted. Results: A significant observation was the prevalence of high-grade (II-III) and undifferentiated tumors across both datasets, accounting for 93.5% in the SEER cohort and 95% in the SZSPH cohort, highlighting the aggressive nature of IMPC. Lymph node metastasis was notably prevalent among the patients, with 54.4% in the SEER dataset and an even higher rate of 71% in the SZSPH group, underscoring the propensity for IMPC to spread to lymphatic structures. From the LASSO regression analysis, six factors emerged with nonzero coefficients, signifying their statistical significance in relation to BCSS. Of note, LNR emerged as the most influential prognostic factor, followed by T-stage, radiotherapy, surgery, ER status, and chemotherapy, respectively. By incorporating these six significant variables, we developed a nomogram aimed at predicting 3- and 5-year BCSS for IMPC patients, which underwent the calibration and validation phases successfully. Its concordance indexes (C-indexes) for the training, internal validation, and external validation sets were 0.838, 0.871, and 0.758, respectively. The time-dependent receiver operating characteristic (ROC) curves also affirmed its clinical utility. The DCA curves illustrated that our nomogram provided greater net clinical benefits for predicting 3- and 5-year BCSS across all three cohorts. In the training set, the nutritional risk indexes (NRIs) for 3- and 5-year BCSS were 0.37 (95% CI 0.286–0.545) and 0.295 (95% CI 0.226–0.418), respectively, while the integrated discrimination improvement (IDI) values for the same time intervals were 0.043 (95% CI 0.035–0.235, P < 0.001) and 0.163 (95% CI 0.025–0.197, P < 0.001). These findings were corroborated in both the internal and external validation sets. In the final step, we computed risk scores for each patient utilizing the developed nomogram and proceeded with risk stratification: low risk (points <90.4) and high risk (points ≥90.4). Kaplan–Meier survival curves exhibited pronounced discrimination between the low-risk and high-risk subgroups, underscoring the nomogram's ability to effectively stratify patients based on their prognosis. Conclusions: In the context of treating patients with IMPC, the LNR has emerged as a robust prognostic indicator. Utilizing LNR as a key parameter, we developed a nomogram designed to offer a practical and dependable method for predicting BCSS in patients with IMPC. This innovative tool serves to facilitate the identification of patients at high risk of adverse outcomes, providing clinicians with valuable insights to guide decision-making in patient care. Citation Format: Yi-Zi Zheng, Yan Liu, Ai-Na Zheng, Yan-Ling Xiao, Er-Jie Xia, Ou-Chen Wang. Survival Nomogram Including Lymph Node Ratio for Patients with Invasive Micropapillary Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-12-15.

Protein Tyrosine Phosphatase Receptor Type Kappa (PTPRK) is a membrane-bound tyrosine phosphatase encoded by the frequently deleted region of chromosome 6q, which plays a crucial role in regulating cell signaling, adhesion, and immune response. Structurally, PTPRK comprises with an extracellular domain involved in cell-cell adhesion, a transmembrane region, and two intracellular catalytic domains responsible for its phosphatase activity. Notably, PTPRK undergoes proteolytic cleavage by Furin and ADAM10, resulting in the generation of an extracellular E-subunit and a P-subunit. Further processing by γ-secretase releases the intracellular PIC, which plays a pivotal role in regulating β-catenin signaling within the nucleus. PTPRK is widely recognized for its tumor-suppressive properties across various cancers, including colorectal, lung, ovarian, and melanoma. Despite its function as a tumor suppressor, the expression and activity of PTPRK exhibit considerable variability across different cancer types and stages. It exerts its effects by dephosphorylating key signaling molecules such as EGFR, STAT3, CD133 and β-catenin, thereby inhibiting cancer cell proliferation, survival, and metastasis. Beyond its role in cancer, PTPRK is also involved in immune regulation, particularly in the development of CD4 + T cells, and has been implicated in autoimmune diseases such as multiple sclerosis. In the nervous system, PTPRK is linked to neurite outgrowth and synaptic transmission, with genetic polymorphisms in PTPRK associated with an increased risk of neurodegenerative diseases like Alzheimer’s disease. Given its extensive involvement in cancer biology, immune regulation, and neurodevelopment, PTPRK presents a promising therapeutic target. Strategies aimed at restoring its activity or targeting PTPRK might offer new approaches for current cancer therapies and overcome drug resistance. In this review, we elucidate the structural characteristics and functional roles of PTPRK in cellular signaling and disease pathogenesis. The variability of PTPRK suggests that the regulatory mechanisms governing its activity are intricate and worth further comprehensive investigation.

Background: To create effective medicines, researchers must first identify the common or unique genes that drive oncogenic processes in human cancers. Serine protease 27 (PRSS27) has been recently defined as a possible driver gene in esophageal squamous cell carcinoma. However, no thorough pan-cancer study has been performed to date, including breast cancer. Methods: Using the TCGA (The Cancer Genome Atlas), the GEO (Gene Expression Omnibus) dataset, and multiple bioinformatic tools, we investigated the function of PRSS27 in 33 tumor types. In addition, prognosis analysis of PRSS27 in breast cancer was carried out, as well as in vitro experiments to verify its role as an oncogene. We first explored the expression of PRSS27 in over 10 tumors and then we looked into PRSS27 genomic mutations. Results: We discovered that PRSS27 has prognostic significance in breast cancer and other cancers' survival, and we developed a breast cancer prognostic prediction model by combining a defined set of clinical factors. Besides, we confirmed PRSS27 as an oncogene in breast cancer using some primary in vitro experiments. Conclusion: Our pan-cancer survey has comprehensively reviewed the oncogenic function of PRSS27 in various human malignancies, suggesting that it may be a promising prognostic biomarker and tumor therapeutic target in breast cancer.