Search Results (5,265)

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by limited treatment options and poor prognosis. Gemcitabine is a commonly used chemotherapy; however, gemcitabine resistance in PDAC poses a critical barrier to effective treatment, as the underlying mechanisms are not yet fully understood. Methods: This study employs an exploratory untargeted metabolomics approach to investigate metabolic differences in PDAC cells in the presence and absence of gemcitabine treatment. HPAF-II, MIA PaCa-2, and BxPC-3 cell lines were used as models for gemcitabine-resistant, moderately responsive, and permissive PDAC cells, respectively. Results: MTT assay results revealed that BxPC-3 cells are highly sensitive to gemcitabine treatment, HPAF-II cells are the most resistant, and MIA PaCa-2 cells exhibit moderate sensitivity. Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) of the metabolomics data demonstrated clear differentiation of gemcitabine-treated and untreated (control) cells. When comparing the treated vs. control conditions, 170 metabolites matched to an in-house library of standards were significant (p < 0.05 or fold change ≥ 2 or VIP ≥ 1) differentiators in HPAF-II cells, whereas MIA PaCa-2 and BxPC-3 cells had 178 and 218 differentiating metabolites, respectively. HPAF-II cells treated with gemcitabine had significantly higher levels of N-acetylneuraminic acid and 7-dehydrocholesterol compared with the control group. In contrast, these metabolites were significantly lower or non-significant in BxPC-3 treated cells. Pathway analysis revealed that the steroid biosynthesis pathway was significantly perturbed in HPAF-II cells, whereas amino sugar and nucleotide sugar metabolism was predominantly altered in BxPC-3 cells. Conclusions: Overall, this exploratory study reveals metabolic differences between treated and untreated cells to derive targeted therapeutic strategies that could be used in the future to improve treatment outcomes for PDAC patients. Full article

Cancer immunotherapy has reshaped oncology, yet durable benefit remains limited for many patients because antitumor responses are constrained by multiple biological and clinical barriers. A targeted narrative review was conducted using peer-reviewed literature indexed in PubMed, Scopus, and Web of Science from January 2020 to April 2026, with additional landmark studies from earlier years included for essential mechanistic context. Priority was given to clinical, translational, and high-impact review articles examining combination strategies built on immune checkpoint blockade and related immune platforms. The evidence was synthesized by the main barriers each strategy aims to overcome, including poor immune priming, immune exclusion, immunosuppressive tumor microenvironments, adaptive resistance, and limited treatment durability. Across recent studies, combination immunotherapy is increasingly moving away from empiric regimen construction toward biologically rational approaches that integrate checkpoint blockade with chemotherapy, radiotherapy, antiangiogenic therapy, targeted agents, antibody–drug conjugates, bispecific antibodies, vaccines, and cellular platforms. Increasing emphasis has also been placed on integrated biomarkers that combine tumor-intrinsic, immune, spatial, and dynamic features to improve patient selection. At the same time, growing regimen complexity continues to raise challenges related to overlapping toxicity, sequencing, polypharmacy, and multidisciplinary implementation. Overall, the field is evolving toward mechanism-matched, biomarker-guided, and clinically manageable strategies that may broaden and refine the benefit of cancer immunotherapy. Full article

Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited therapeutic options in advanced and recurrent diseases. Advanced PSCC is typically managed with multimodal therapy, including neoadjuvant chemotherapy or chemoradiation followed by surgery; however, durable responses remain uncommon, and outcomes after recurrence are poor. Cancer vaccines represent a promising immunotherapeutic strategy, as these treatments induce tumor-specific immunity and heightened immune surveillance against penile cancer cells. While therapeutic cancer vaccines have not yet demonstrated consistent clinical efficacy as monotherapy in PSCC, their integration with complementary immune-modulating approaches, particularly immune checkpoint blockade, represents a rational strategy to enhance antitumor immunity. This review summarizes the rationale for vaccine development in PSCC, with emphasis on HPV-derived antigens, neoantigens, and emerging tumor-associated targets. We examine major vaccine platforms, including viral-vector, peptide-based, nucleic acid, and dendritic cell-based approaches. We also discuss how spatial transcriptomics, single-cell RNA sequencing, artificial intelligence-assisted antigen prediction, and nanotechnology-enhanced delivery systems may support future personalized vaccine development. Overall, therapeutic vaccines remain investigational in PSCC but may become relevant within biomarker-driven, combination-based immunotherapy strategies. Full article

Cytoreductive surgery remains one of the key treatment modalities in advanced ovarian cancer. Complete cytoreduction is the main surgical goal. PARP inhibitors are currently established mainly as maintenance therapy after response to platinum-based chemotherapy, particularly in patients with BRCA-mutated or homologous recombination-deficient tumors. Their use before cytoreductive surgery remains investigational. This review evaluates preoperative PARP inhibition from a surgical perspective. This narrative review summarizes current evidence, ongoing clinical trials, and perioperative considerations related to preoperative or neoadjuvant PARP inhibitor strategies in advanced ovarian cancer. Particular attention was given to the review of current clinical trials’ strategies, resectability, complete cytoreduction, patient selection, perioperative safety, treatment timing, and surgery-specific endpoints. Current studies explore several preoperative approaches, including short window-of-opportunity treatment before primary debulking surgery, PARP inhibitor monotherapy as potential conversion therapy in homologous recombination-deficient disease, PARP inhibitor-based strategies before interval debulking surgery, combination regimens with immunotherapy or antiangiogenic therapy, and preoperative PARP inhibitor use before secondary cytoreduction in recurrent disease. These studies suggest that preoperative PARP inhibition may provide biological and surgical insights, but available evidence remains preliminary. Key concerns include hematologic toxicity, surgical postponement, perioperative complications, wound healing, postoperative recovery, and the risk of delaying standard chemotherapy or surgery. Preoperative PARP inhibitor therapy is theoretically promising but an unproven strategy in ovarian cancer. Its future value will depend on prospective trials showing that it can safely improve resectability and complete cytoreduction without compromising treatment timing. Future studies should include surgery-specific endpoints in addition to conventional oncologic outcomes. Full article

Background/Objectives: Despite improved survival with immune checkpoint inhibitors, the optimal treatment after anti-PD-1 progression in metastatic melanoma remains unclear. This study compared survival outcomes and treatment responses between chemotherapy (CT)- and immunotherapy (IO)-based therapies administered after nivolumab progression in patients with BRAF-negative metastatic melanoma. Methods: This multicenter retrospective study included patients with BRAF-negative metastatic melanoma who developed disease progression during nivolumab treatment. Post-progression systemic therapies were categorized as CT- or IO-based treatments. Treatment responses were assessed according to RECIST version 1.1 criteria. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan–Meier method, and prognostic factors were evaluated using Cox regression analyses. Results: A total of 141 patients were included. Following nivolumab progression, 107 (75.9%) received CT and 34 (24.1%) received IO. Based on best response to nivolumab, the objective response rate (ORR; CR + PR) was 55.1% in the CT group and 44.1% in the IO group. After post-nivolumab treatment, ORRs were 29.9% and 32.4% in the CT and IO groups, respectively, whereas complete response rates were higher with IO (21.2% vs. 3.0%). Median PFS was 4.17 months in the CT group and 3.9 months in the IO group (p = 0.403). Median OS was 7.83 and 8.17 months, respectively (p = 0.416). Elevated LDH level was identified as an independent adverse prognostic factor. Conclusions: In this multicenter real-world cohort, no statistically significant differences in survival were observed between patients receiving CT or IO after nivolumab progression. Given the retrospective, non-randomized study design, these findings should not be interpreted as evidence of comparative treatment efficacy. The higher CR rate observed with IO should be interpreted cautiously due to potential selection bias. Prospective studies are warranted to define the optimal treatment strategy after anti-PD-1 failure. Full article

Background/Objectives: Doxorubicin (DOX) is an effective chemotherapeutic agent, but its clinical use is limited by dose-dependent cardiotoxicity. Emerging evidence suggests that epigenetic dysregulation, particularly altered DNA methylation, contributes to DOX-induced cardiac injury. Metformin has been reported to exert cardiometabolic and epigenetic regulatory effects. This study investigated genome-wide DNA methylation changes induced by chronic metformin exposure and their effects on doxorubicin sensitivity in H9c2 cardiomyoblast cells. Methods: Genome-wide DNA methylation changes induced by chronic metformin exposure were investigated in H9c2 cardiomyoblast cells using whole-genome bisulfite sequencing (WGBS). Cells were treated with metformin (0.7–2.8 mM) for four months prior to DOX exposure. Cellular sensitivity to DOX was evaluated using MTT-based dose–response analysis and IC₅₀ estimation. Results: DOX reduced cell viability (IC₅₀ = 0.164 µM). Chronic metformin pre-treatment produced a dose-dependent rightward shift in DOX dose–response curves, increasing IC₅₀ values to 0.21, 0.289, and 0.51 µM at 0.7, 1.4, and 2.8 mM metformin, respectively. WGBS revealed distinct separation between treatment groups in principal component analysis. Significant methylation changes (adjusted p-value < 0.05) were identified in genes related to oxidative stress, mitochondrial function, apoptosis, and chromatin regulation. Conclusions: Chronic metformin exposure induces dose-dependent genome-wide DNA methylation remodeling in cardiac cells and is associated with altered cellular sensitivity to doxorubicin. These findings suggest that metabolic modulation by metformin may influence epigenetic regulation and cellular stress responses relevant to chemotherapy-induced cardiotoxicity. Full article

Ganoderma lucidum polysaccharide peptide (GLPP) is a food-derived macromolecule with immunomodulatory potential, but its gut-centered mechanisms under chemotherapy-associated immunosuppressive stress remain unclear. This study aimed to evaluate the protective effects of GLPP against cyclophosphamide (CTX)-induced immunosuppression and intestinal injury in mice and to explore the associated microbiota–metabolite–gene interaction network using integrated foodomics. BALB/c mice were treated with CTX and then administered GLPP at 50, 100, or 200 mg/kg/day for 42 days, with levamisole as a positive control. High-dose GLPP restored spleen index from 1.592 ± 0.266 to 1.902 ± 0.212 mg/g and thymus index from 0.322 ± 0.146 to 0.656 ± 0.081 mg/g compared with the CTX group. It also enhanced lymphocyte proliferation (OD450: 1.529 ± 0.073 vs. 1.065 ± 0.051), increased carbon clearance index (3.403 ± 0.223 vs. 2.650 ± 0.164), elevated IL-2 and IgA levels, and reduced excessive IFN-γ and TNF-α responses. GLPP alleviated intestinal mucosal injury and reshaped gut microbial profiles, particularly taxa related to Bacteroidota and Bacteroides. Metabolomics revealed putatively annotated differential metabolites associated with amino acid, nicotinate–nicotinamide, and glycerophospholipid metabolism, while transcriptomics indicated modulation of PRR/MAPK-related immune signaling. Integrated correlation analysis suggested a microbiota–metabolite–gene–immune association network involving putative gamma-Glutamylleucine(γ-Glu-Leu), leukotriene D4(LTD4)-like lipid features, and hippuric acid. These findings support GLPP as a promising immune-supporting functional food ingredient, although metabolite assignments and causal mechanisms require further validation. Full article

Background/Objectives: Peritoneal metastases (PMs) arise from gastrointestinal, gynecologic, hepatobiliary, and colorectal origins and are associated with poor outcomes. Cytoreductive surgery (CRS) with intraperitoneal (IP) chemotherapy offers benefit for select patients, but survival remains limited. This review aims to summarize recent insights into the molecular and tumor microenvironmental (TME) changes characteristic of PMs and the impact of IP chemotherapy. Methods: A literature review was performed using recent clinical, translational, and preclinical studies examining alterations in molecular signaling, DNA repair alterations, metabolic pathways, and angiogenic factors in PMs before and after IP therapy. Results: Peritoneal metastases exhibit distinct biology after being treated with IP chemotherapy. Treatment induces alterations in gene expression, mutational patterns, and immune infiltrates. Heated intraperitoneal chemotherapy (HIPEC) has been associated with increased CD8+ T-cell activity, macrophage and NK cell shifts, and modulation of PD-1/PD-L1 signaling, which correlate with treatment response and survival. Emerging data on PIPAC similarly suggests induction of favorable gene expression changes with repeated treatment, though supporting evidence remains more limited than for HIPEC. Angiogenic pathways—particularly VEGF and HIF1α—remain key drivers of PM progression and predictors of post-operative outcomes. Early findings suggest potential synergy between IP chemotherapy and immunotherapy though clinical trials are ongoing. Conclusions: IP chemotherapy induces tumor microenvironmental changes that have potential to shape therapeutic response. Characterizing these measurable biologic changes may allow clinicians to improve patient selection and support the development of combination therapies to enhance outcomes. Full article

Background: Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality worldwide over the past decade. Single-cell sequencing loses spatial location information and potential cell–cell interactions, making it difficult to interpret molecular features or biological phenomena. Tertiary lymphoid structures (TLSs) inherently require such spatial immune cell distribution information. Although associations between TLS and response to immune checkpoint inhibitors (ICIs) or chemotherapy have been reported, the relationship between TLS and neoadjuvant therapy (ICI combined with chemotherapy) remains unclear. Methods: We performed spatial transcriptomics on NSCLC samples (including one lung squamous cell carcinoma (LUSC) and one lung adenocarcinoma (LUAD)). Multiplex immunohistochemistry (mIHC) was used to identify the TLS, while immunohistochemistry staining (IHC) was used to identify the TLS status and cell characteristics. We evaluated the associations between (mature) TLS density, area proportion and patients’ responses in 66 patients. Results: Heterogeneity of immune cells in NSCLC was found. Gene ontology analysis and cell score comparison identified TLS with activated B and T cells inside, while plasma cells and macrophages were mainly distributed outside TLS. Four genes from antigen-presenting machinery (TAP1, TAP2, B2M, TAPBP) were more highly expressed inside TLS than outside them. Also, TLS exhibited heterogeneity, with both mature and immature TLS. Mature TLS showed an average area of 62,387.43 μm², while the immature TLS showed 51,189.90 μm². The Spearman correlation coefficient of B-cell number and mTLS area showed r = 0.900. TLS density and mature TLS (mTLS) density in the tumor bed were 1.95 ± 0.95 TLS/10 mm² (mean ± SD, n = 34) and 1.13 ± 0.77 mTLS/10 mm², significantly higher than that in the non-responder group (1.18 ± 1.15 TLS/10 mm², 0.70 ± 0.90 mTLS/10 mm², mean ± SD, n = 32) separately. B cells belonging to TLS had a significantly higher density (71.32 ± 55.71 cells/mm², mean ± SD, n = 34) in the responder group than the non-responder group (61.33 ± 111.95 cells/mm², mean ± SD, n = 32) normalized to the tumor bed area. Conclusions: Spatial transcriptomics reveals immune cell heterogeneity and distribution patterns in the NSCLC tumor bed, with activated B and T cells localized inside and plasma cells/macrophages outside. Antigen-presenting machinery (APM)-related genes were highly expressed in TLS accompanied by a high expression of upstream and downstream genes of MHC class I. mTLS have a larger area by mainly containing more B cells. The responder group had a significantly higher (mature) TLS density and larger (mature) TLS area proportion compared with the non-responder group, suggesting their potential function in anti-tumor effect in neoadjuvant treatment. Full article

Gemcitabine-based chemotherapy has long served as a standard treatment for urothelial carcinoma (UC), particularly in perioperative and metastatic settings. However, therapeutic efficacy is frequently limited by intrinsic or acquired resistance. Gemcitabine functions as a prodrug whose activity depends on coordinated processes involving cellular uptake, intracellular activation, metabolic inactivation, and nucleotide metabolism. Increasing evidence suggests that resistance in UC is mediated by multiple interconnected mechanisms beyond alterations in gemcitabine transport, activation, and inactivation alone. Key molecular determinants include human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (dCK), cytidine deaminase (CDA), and ribonucleotide reductase regulatory subunit M1 (RRM1), which is involved in nucleotide pool maintenance and DNA synthesis. In addition, replication stress responses, apoptosis evasion pathways, and tumor microenvironment-associated factors also contribute to gemcitabine resistance. Stress-adaptive pathways involving Y-box binding protein 1 (YB-1), hypoxia-inducible factor-1 alpha (HIF-1α), and autophagy-related mechanisms may further promote survival under chemotherapy-induced stress conditions. In addition, extracellular mucin-associated mechanisms may alter intratumoral drug accessibility and contribute to resistance. In this review, we summarize UC-specific evidence regarding gemcitabine resistance and discuss how these pathways collectively shape an integrated resistant phenotype. Full article

Background: Triple-negative breast cancer (TNBC), devoid of actionable targets for endocrine or HER2-directed therapy, is highly aggressive with elevated risks of recurrence and metastasis; surgical resection remains the mainstay of treatment, and postoperative chemotherapy serves as a key adjuvant modality for controlling residual disease. Doxorubicin (DOX), although widely used, shows limited tumor selectivity, considerable systemic toxicity, and poor control over drug release at the tumor site. To address these issues, we developed near-infrared (NIR)-responsive gold-decorated phase-change nanodroplets (AuNPs-DOX-NDs) that combine photothermal conversion, liquid-to-gas phase transition, and controlled DOX release in a single platform. Methods: The nanodroplets consisted of a perfluorohexane (PFH) core, a DOX-loaded lipid shell, and polyethyleneimine-modified gold nanoparticles (PEI-AuNPs) conjugated to the surface as the NIR photothermal component. Physicochemical characterization was performed to evaluate morphology, colloidal dispersity, and storage stability. Under 808 nm laser irradiation, the photothermal behavior, PFH vaporization, and DOX release properties of AuNPs-DOX-NDs were investigated. In vitro studies using 4T1 TNBC cells were conducted to assess intracellular DOX accumulation, cell proliferation, migration, and apoptosis. Results: Physicochemical characterization showed that the nanodroplets had a uniform nanoscale morphology, good colloidal dispersity, and acceptable storage stability. Under 808 nm laser irradiation, AuNPs-DOX-NDs exhibited concentration-dependent photothermal heating, which induced PFH vaporization and accelerated DOX release, indicating a clear stimulus-responsive release behavior. In vitro studies using 4T1 TNBC cells showed enhanced intracellular DOX accumulation after treatment with AuNPs-DOX-NDs. Upon laser irradiation, the nanodroplets further inhibited cell proliferation and migration and promoted apoptosis, suggesting an enhanced combined photothermal–chemotherapeutic effect in 4T1 TNBC cells. Conclusions: These results indicate that AuNPs-DOX-NDs may serve as a useful NIR-responsive platform for externally controlled drug release and enhanced combined photothermal-chemotherapy, and deserve further evaluation in vivo. Full article

Backgrounds: Bladder cancer shows pronounced biological heterogeneity that underlies its variable clinical course and prognosis. Our study aims to delineate clinically relevant differences in bladder cancer using an immunohistochemistry-based molecular subtyping approach. Methods: This retrospective study included 590 patients with bladder cancer treated at a single center. Tumors were stratified into luminal versus non-luminal categories according to CK20, GATA3, CK5/6, and CK14. Associations between molecular subtype, histopathological growth patterns, pathological response to neoadjuvant chemotherapy (NAC), and clinical survival endpoints were analyzed. Overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS) were evaluated through Kaplan–Meier survival curves together with Cox proportional hazards regression analyses. Results: Non-luminal tumors exhibited significantly more aggressive pathological growth patterns, including higher levels of tumor budding (p = 0.002), a predominance of non-cohesive or spindle/single-cell architecture (p = 0.003), and more frequent disseminated spreading patterns (p = 0.001), whereas luminal tumors more commonly displayed a higher frequency of tertiary lymphoid structures (TLSs; p = 0.041). Among patients receiving NAC, non-luminal tumors achieved a significantly higher pathological complete response (pCR) rate compared with luminal tumors (p = 0.007), while no significant inter-subtype difference was detected in pathological downstaging between subtypes (p = 0.126). Despite inferior pathological response, luminal tumors demonstrated significantly improved OS (p = 0.003), RFS (p = 0.002) and PFS (p < 0.001) compared with non-luminal tumors. In multivariable Cox regression analysis, molecular subtype was identified as an independent predictor of OS, with luminal tumors showing a lower mortality risk (HR = 0.51, 95% CI 0.33–0.79, p = 0.003). Conclusions: These findings indicate that pathological response and long-term survival follow distinct, subtype-dependent trajectories in bladder cancer. Favorable pathological response does not necessarily correspond to improved long-term survival across molecular subtypes. Full article

Chagas disease, caused by Trypanosoma cruzi, remains a major public health problem in Latin America and an emerging global health concern due to population mobility. Although benznidazole and nifurtimox remain the only approved antiparasitic drugs, their limited efficacy in chronic infection, prolonged treatment regimens, frequent adverse effects, and variable activity across parasite strains highlight the need for new therapeutic strategies. In addition, the pathogenesis of chronic Chagas disease is driven not only by parasite persistence but also by immune-mediated tissue damage, particularly in chronic Chagas cardiomyopathy. In this review, we examine emerging therapeutic approaches that extend beyond conventional trypanocidal chemotherapy, with emphasis on natural products, antimicrobial peptides, and cell-based immunomodulatory strategies. Plant compounds and essential oils have shown antiparasitic activity through mechanisms including oxidative stress induction, membrane disruption, interference with sterol biosynthesis, and mitochondrial dysfunction, while some extracts also modulate host immune responses. Antimicrobial peptides display dual potential by directly damaging parasite membranes and organelles or by reshaping infection-associated inflammatory responses. In parallel, cell-based therapies such as mesenchymal stromal cells, tolerogenic dendritic cells, and bone marrow-derived cells have demonstrated promising cardioprotective and immunoregulatory effects in experimental chronic Chagas disease. Collectively, these approaches support a multitarget therapeutic framework in which parasite-directed and host-directed interventions may complement each other. Further mechanistic studies, standardization, and translational validation will be essential to advance these candidates toward clinically useful therapies for Chagas disease. Full article

Resistance to 5-fluorouracil (5-FU) remains a major limitation in colorectal cancer therapy, prompting the development of combination strategies aimed at improving its efficacy. Bakuchiol (BAK), a natural compound with reported antioxidant and pro-oxidant properties, may modulate redox balance and enhance chemotherapy response. This study compared the effects of 5-FU and BAK, applied as monotherapies and in combination, in DLD-1 and HT-29 colorectal cancer cells. Cytotoxicity assays showed that co-treatment significantly reduced the IC₅₀ of 5-FU, particularly in DLD-1 cells, and revealed an enhanced anticancer effect of the combination treatment compared with either monotherapy. Flow cytometric analyses demonstrated enhanced apoptosis via extrinsic and intrinsic pathways, including increased caspase 8 activity, loss of mitochondrial membrane potential (ΔΨ_m), activation of caspase 9, and subsequent activation of caspases 3/7. These effects were associated with a pronounced redox imbalance, reflected by increased intracellular reactive oxygen species (ROS) levels, suggesting a central role of oxidative stress in mediating cytotoxicity. Antioxidant pre-treatment attenuated ROS accumulation and reduced apoptosis, confirming a causal relationship. Additionally, autophagy was induced selectively in DLD-1 cells, indicating cell-line-specific differences in redox adaptation. Taken together, BAK enhances 5-FU efficacy through ROS-dependent activation of mitochondrial and caspase-dependent pathways, with stronger effects observed in DLD-1 cells. Full article

Background and Objectives: The HER2-low designation has emerged as a clinically actionable category in breast cancer following the approval of trastuzumab deruxtecan for HER2-low metastatic disease. However, the clinical relevance of HER2-low expression in the neoadjuvant chemotherapy (NAC) setting remains uncertain. This study aimed to evaluate pathological complete response (pCR) as the primary endpoint and overall survival (OS) and disease-free survival (DFS) as exploratory secondary endpoints across HER2-low, HER2-zero, and HER2-positive subgroups in a NAC-treated cohort. Materials and Methods: This single-center retrospective cohort study included 118 patients with histopathologically confirmed invasive breast cancer who received NAC at our institution between January 2010 and March 2021. Patients were classified as HER2-zero (IHC 0, n = 66), HER2-low (IHC 1+ or IHC 2+/FISH-non-amplified, n = 17), or HER2-positive (IHC 3+ or IHC 2+/FISH-amplified, n = 35). pCR was defined as ypT0/Tis ypN0. Univariate analyses used χ² or Fisher’s exact tests; multivariable logistic and Cox regression were performed for adjusted analyses, and Kaplan–Meier survival curves were compared by log-rank, Breslow, and Tarone–Ware tests. Results: The overall pCR rate was 24.6%, differing significantly across HER2 subgroups (HER2-positive 45.7%, HER2-low 29.4%, HER2-zero 12.1%; p = 0.001). After multivariable adjustment for age, ER, PR, and tumor grade, HER2-positive status retained an independent association with pCR (OR 4.37, 95% CI 1.46–13.10, p = 0.008), whereas HER2-low status did not (OR 2.65, 95% CI 0.60–11.75, p = 0.201). At a median follow-up of 48.8 months, neither OS (log-rank p = 0.567) nor DFS (log-rank p = 0.901) differed significantly across HER2 subgroups, and HER2 subgroup status was not independently associated with survival in exploratory Cox models. Conclusions: In this NAC-treated cohort, the unadjusted pCR advantage of HER2-low over HER2-zero tumors was not retained after adjustment for hormone receptor expression and tumor grade, and no HER2 subgroup-specific survival difference was demonstrated. Within the standard NAC framework, HER2-low disease did not show a pCR or survival pattern clearly distinct from HER2-zero disease after adjustment; the small HER2-low subgroup and wide confidence intervals preclude firm conclusions, and an exploratory hormone receptor-stratified analysis indicated that the apparent pooled HER2-low advantage was confined to the hormone receptor-negative subgroup. Future prospective studies powered for hormone receptor-stratified analyses are warranted. Full article