Search Results (2,930)

Background/Objectives: Breast cancer exhibits substantial molecular heterogeneity, resulting in diverse therapeutic vulnerabilities and limiting the efficacy of single-agent therapies. Although multi-target strategies may offer improved therapeutic benefit, the systematic identification of synergistic higher-order target combinations remains challenging. This study aimed to identify and validate effective higher-order target combinations for heterogeneous breast cancer. Methods: DeepMDS, a previously developed deep learning-based multi-compound synergy prediction model, was used to prioritize candidate target combinations for breast cancer. Exhaustive two-target and three-target combinations were ranked in the gene-expression contexts of ER-positive luminal-like MCF-7 and triple-negative MDA-MB-231 breast cancer cells. The top-ranked target combinations were evaluated using single, pairwise, and triple small interfering RNA (siRNA) perturbations. Representative inhibitors were subsequently assessed in fixed-ratio combinations in MCF-7, MDA-MB-231, and 4T1 cells and in a 4T1 syngeneic mouse experiment. Results: BIRC5-NAMPT-TOP1 ranked first in both cell lines. Triple siRNA co-transfection targeting BIRC5, NAMPT, and TOP1 produced the strongest antiproliferative effects, with inhibition rates of 62.94% in MCF-7 cells and 55.62% in MDA-MB-231 cells. The corresponding inhibitors, LQZ-7I, FK866, and topotecan, exhibited synergistic antiproliferative activity at multiple molar ratios, with combination index values below 1. The optimized 2.5:10:1 molar ratio showed strong synergy in MCF-7, MDA-MB-231, and 4T1 cells, with combination index values of 0.26, 0.19, and 0.15, respectively. In tumor-bearing mice model, the triple-inhibitor regimen achieved a tumor inhibition rate of 62.05%. Topotecan-containing groups showed hematological alterations, whereas no statistically detectable elevations were observed in the measured terminal serum hepatic or renal biomarkers. Conclusions: The BIRC5-NAMPT-TOP1 combination showed reproducible phenotypic activity in the tested genetic and pharmacological models. These findings support the use of DeepMDS as a hypothesis-generation tool for higher-order target prioritization. Full article

Interleukin-12 (IL-12) potently promotes the recruitment and activation of immune cells within the tumor microenvironment (TME), highlighting its immense potential for cancer therapy. However, its dose-limiting systemic toxicity and short half-life severely hinder its clinical translation. Here, we design a tumor-conditionally activated IL-12 prodrug termed αHSA-proIL-12. This engineered molecule integrates a cleavable albumin-binding nanobody (αHSA) domain to extend the half-life and enhance tumor targeting alongside a masking domain that occludes the IL-12 receptor-binding site to prevent nonspecific activation. This construct undergoes selective cleavage by matrix metalloproteinases (MMPs) that are highly expressed in the TME to release highly penetrant, free, low-molecular-weight IL-12 locally. This tumor-restricted activation process directly facilitates the selective recruitment and activation of tumor-infiltrating lymphocytes (TILs). The intravenous administration of an extremely low dose of 108 pmol per dose of αHSA-proIL-12 completely cleared MC38 tumors without inducing systemic toxicity. The maximum tolerated dose of this molecule exceeded 2 nmol, yielding a remarkably wide therapeutic index >18.5. Mechanistically, αHSA-proIL-12 effectively reprogrammed the immunosuppressive TME by expanding the numbers of effector CD8⁺ T cells and natural killer cells while upregulating IFN-γ expression and significantly reducing the proportion of regulatory T cells. This immunological remodeling has the potential to convert “cold” tumors into “hot” tumors. Notably, this treatment achieved complete regression and durable immunity in a subset of mice with multiple refractory immune-cold tumors, including Panc02 pancreatic cancer, 4T1 triple-negative breast cancer, and B16F10 melanoma, when administered as a monotherapy or in combination with PD-L1 blockade. Furthermore, when combined with surgery, αHSA-proIL-12 effectively prevented the postoperative recurrence and distant metastasis of advanced 4T1 tumors. This modular platform provides a clinically promising strategy to overcome the toxicity bottleneck of cytokines and substantially advances the development of combination cancer immunotherapies. Full article

Dual inhibition of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT) has emerged as a promising therapeutic strategy due to its ability to simultaneously target oncogenic signaling and cellular metabolism in cancer. While existing inhibitors such as KPT9274 and PF-3758309 have demonstrated preclinical activity, their clinical translation has been limited by poor selectivity, suboptimal efficacy, and dose-limiting toxicities. Reliance on a small number of available compounds is therefore insufficient, highlighting the need for systematic optimization to identify candidates with improved therapeutic profiles. Although several dual PAK4 and NAMPT inhibitors such as GNE2861, LCH7749944, and PF3758309 have been identified in our previous study, the number of compounds available is limited. Identification of new candidate compounds would allow researchers to identify those that are the most efficient, those that are the most potent and selective, and those that have optimal pharmacokinetics. In this study, we performed additional large-scale drug screening to identify new candidate dual PAK4 and NAMPT inhibitors and expand the diversity of this inhibitor class. Computational molecular docking was used to evaluate binding affinities toward both targets, followed by drug–protein interaction analyses to assess binding stability and interaction patterns at the molecular level. Several new candidate compounds demonstrated favorable predicted binding to both PAK4 and NAMPT, with distinct interaction profiles compared to previously reported inhibitors. Biochemical assays further demonstrated inhibitory activity against both PAK4 and NAMPT among several selected compounds, supporting their potential as dual-target inhibitors. These findings provide mechanistic insight into dual-target engagement and highlight structural features associated with improved binding behavior. Expanding the pool of dual inhibitors enhances opportunities for preclinical development, supports optimization of pharmacokinetic and safety profiles, and strengthens datasets for drug discovery. Collectively, this work broadens the landscape of dual PAK4 and NAMPT inhibitors and supports their potential application across multiple cancer types beyond triple-negative breast cancer. Full article

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype lacking effective targeted therapies. Its tumor microenvironment (TME) exhibits distinct features, including acidity, redox imbalance, elevated reactive oxygen species (ROS), and hypoxia, which provide exploitable triggers for targeted drug delivery. Stimuli-responsive polymeric nanocarriers have emerged as promising platforms that enable spatiotemporally controlled and site-specific therapeutic release in response to these endogenous cues, as well as exogenous stimuli such as temperature and light. These systems improve drug accumulation, penetration, and therapeutic efficacy while reducing systemic toxicity. Unlike previous reviews that broadly discuss nanocarriers in cancer therapy, this review focuses on the structure–function relationships of TME-responsive polymeric systems in TNBC and their translational limitations. We summarize recent advances in pH-, redox-, ROS-, hypoxia-, photo- and temperature-responsive polymers, highlighting their design strategies and therapeutic applications. Key challenges, including stimulus heterogeneity, limited in vivo validation, and clinical translation barriers, are also discussed. This review provides a concise framework for the rational design of programmable, multi-responsive polymeric nanomedicines for TNBC therapy. Full article

Purpose: Pembrolizumab combined with chemotherapy is the standard of care for early-stage triple-negative breast cancer (TNBC) following KEYNOTE-522. However, real-world data on immune-related adverse events (irAEs) remain limited. We evaluated the incidence, severity, and clinical consequences of irAEs in a real-world cohort and compared outcomes with KEYNOTE-522. Methods: We conducted a retrospective cohort study of patients with stage II–III TNBC treated according to the KEYNOTE-522 regimen at two Ontario cancer centres between June 2022 and May 2024. Data on irAEs, treatment discontinuation, and pathological complete response (pCR) were collected and contextualized against trial outcomes. Results: Among 79 patients, the pCR rate was higher than that reported in KEYNOTE-522 (77.2% vs. 64.8%). irAEs were documented in 51.9% of patients, compared with 33.5% in the trial. Permanent discontinuation due to irAEs occurred in 22.8% of patients, compared with 15.7% reported in KEYNOTE-522. Most discontinuations occurred during the neoadjuvant phase. Conclusions: Real-world patients experienced higher observed rates of low-grade irAEs and treatment discontinuation than reported in KEYNOTE-522; however, differences in study design limit direct comparison. These findings highlight the need for optimized toxicity management and further study of the impact of treatment duration on long-term outcomes. Full article

Adjuvant and perioperative immune checkpoint inhibitors (ICIs) have created a growing population of patients who relapse after prior programmed death-1 or programmed death-ligand 1 blockade, yet these patients were underrepresented in many trials that established metastatic standards. We performed a structured narrative review of PubMed/MEDLINE, ClinicalTrials.gov, reference lists, and international oncology guideline repositories through 15 August 2026. Eligible reports addressed recurrence patterns or treatment after curative-intent ICI in melanoma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), urothelial carcinoma, or triple-negative breast cancer (TNBC); landmark metastatic studies were included only when direct evidence was unavailable and are labeled as extrapolation. Timing was standardized as on-treatment recurrence, early off-treatment recurrence (after the last ICI dose through 12 months), and late recurrence (>12 months). Shorter disease-free interval is consistently prognostic, but treatment-by-timing interactions are rarely available; timing should not be described as a validated pan-tumor predictive biomarker. Direct post-adjuvant evidence supports switching away from anti-PD-1 monotherapy for melanoma recurring on treatment, while selected late relapses may retain sensitivity. In RCC, retrospective post-adjuvant data support VEGF-targeted options, whereas CONTACT-03 and TiNivo-2 discourage routine ICI-TKI rechallenge specifically after prior ICI-treated metastatic RCC. Evidence in NSCLC, urothelial carcinoma, and TNBC is largely indirect. IMpassion132 was not an ICI-rechallenge trial, and only a small minority of ASCENT-04 participants had prior perioperative ICI. Treatment should integrate tumor-specific biology, actionable alterations, recurrence distribution, prior toxicity, comorbidity, access, and patient preference. Prospective trials dedicated to post-adjuvant ICI recurrence are needed. Full article

Background/Objectives: Triple-negative breast cancer (TNBC) exhibits substantial metabolic heterogeneity and plasticity, contributing to variable therapeutic responses. We investigated whether optical redox imaging (ORI) could characterize metabolic phenotypes, monitor responses to metabolic perturbation, and relate these responses to functional outcomes in TNBC cells. Methods: Four TNBC cell lines were treated with the lactate dehydrogenase A inhibitor FX11 or the glutaminase inhibitor CB-839, alone or in combination with paclitaxel. Intensity-based label-free ORI was performed and followed by imaging of fluorescent probes to assess mitochondrial membrane potential (MMP), re-active oxygen species (ROS), and cell number in the same dishes. Seahorse assays were used to evaluate mitochondrial respiration and glycolytic flux. Results: TNBC cell lines exhibited distinct basal redox phenotypes and differential responses to acute glycolytic and glutaminolytic perturbation. HCC1806 cells showed the strongest acute ORI responses to both FX11 and CB-839. Acute FX11 treatment induced a rapid reductive shift accompanied by ROS accumulation and loss of MMP, whereas CB-839 produced a more modest early reductive response without detectable ROS accumulation or MMP loss. Prolonged treatment revealed distinct temporal redox trajectories in HCC1806 cells: FX11-treated cells evolved from an acute reductive response toward a more oxidized state, while CB-839-treated cells transitioned from an early reductive shift to a sustained oxidized redox state accompanied by marked reductions in OCR and ECAR. Functionally, in two representative models (HCC1806 and MDA-MB-231), CB-839 reduced cell numbers and enhanced the anti-proliferative effect of paclitaxel, whereas FX11 had no significant effect on cell number despite inducing pronounced acute redox perturbations. Conclusions: Integrating ORI with metabolic flux assays and imaging-based functional measurements enables characterization of multiple dimensions of metabolic behavior, including basal phenotype, pathway-specific responsiveness, temporal redox responses, and treatment-associated outcomes. These findings support intensity-based wide-field ORI as a practical and accessible tool for probing metabolic heterogeneity and characterizing context-dependent metabolic responses in TNBC cells. Full article

Background/Objectives: Breast cancer (BC) is the most frequently diagnosed malignancy and a leading cause of cancer-related mortality in women worldwide. This disease is highly heterogeneous and dynamic, and chromosomal instability (CIN) plays a key role in the acquisition of these traits by generating genetic diversity that promotes tumor adaptation and influences therapeutic response and prognosis. Although several methods have been developed to quantify CIN, they are not readily applicable to human tumors and are limited in resolution, hindering a comprehensive understanding of intratumoral heterogeneity. In this study, we aimed to quantify CIN levels and clonal heterogeneity (CH) in HER2-positive (HER2+) and triple-negative (TNBC) breast cancer using single-cell RNA sequencing (scRNA-seq) data. Methods: We analyzed publicly available scRNA-seq data from HER2+ and TNBC tumors and non-malignant controls. CIN was scored at single-cell resolution using transcriptomic signatures, clonal heterogeneity was estimated from single-cell diversity metrics, and copy number alterations were inferred computationally. Differential expression and functional enrichment analyses were performed between cells with very low and extreme CIN levels, with key comparisons confirmed at the patient level. Results: Our analyses revealed pronounced intra- and intertumoral heterogeneity, with higher CIN levels in TNBC than in HER2+ and control samples. Genes differentially expressed in cells with extreme CIN values were mainly involved in cell division and related processes, and included candidate biomarkers not previously reported in this context. Our findings suggest a positive but statistically non-significant trend was observed between CIN and CH. Conclusions: Single-cell approaches such as scRNA-seq provide a powerful framework to elucidate CIN-related mechanisms and to identify potential biomarkers of BC aggressiveness and prognosis, supporting their further application in the study of intratumoral heterogeneity. Full article

Functional studies have shown that long noncoding RNAs (lncRNAs) play different roles in gene expression regulation, acting as epigenetic factors. Accumulating evidence indicates that lncRNAs modulate diverse biological processes, and their altered expression is associated with the development and progression of cancer, including BC. Here, aiming to identify lncRNAs associated with breast cancer, we performed a re-analysis of the expression data from 1071 tumors of eligible patients in the LACRN-MPBC Study. Using normalized data, we compared the expression profiles of triple-negative breast cancer (TNBC; 170 cases) and a heterogeneous group of non-TNBC tumors (782 cases). A total of 59 differentially expressed lncRNAs (DELncRNAs) could be identified based on the criteria of |log2FC| ≥ 1 and FDR < 0.05, using the DESeq2 R package. In the Kaplan–Meier survival analysis, we identified DELncRNAs that affect disease-free survival and/or overall survival, with eight of them in TNBC and 27 in non-TNBC patients. Multivariate Cox proportional-hazards models were used to evaluate independent predictors of survival. Two DELncRNAs, VLDLR-AS1 and PART1, were identified as independent prognostic markers for TNBC patients, while seven (LINC00239, FAM30A, LINC00842, LINC01315, EGOT, LY6E-DT, and SLC25A21-AS1) were independent prognostic markers for non-TNBC patients. Our computational study identifies several candidate lncRNAs associated with clinical outcomes in breast cancer. However, the DELncRNAs identified here should be interpreted as preliminary candidates, which require future validation and functional studies to determine their biological roles and evaluate their potential as prognostic biomarkers. Full article

Background: Age, race, body mass index (BMI), breast density, parity, smoking and alcohol use are associated with increased risk for breast cancer. These factors, as well as tumor characteristics, treatment regimens and comorbidities, are analyzed for associations with five-year event free survival (EFS) in a sample of women with Stage I-III breast cancer who received chemotherapy with curative intent. Methods: EFS was defined in terms of breast cancer recurrence, second primary, metastasis, and overall survival. Analyses were stratified by age (under age 65 vs. over age 65). EFS was estimated using the Kaplan–Meier method and compared using a Cox proportional hazard model. Results: In a sample of 821 women, mean age at diagnosis was 54 years, with 75% White and 22% Black. Younger women had higher proportions of Stage II and III tumors (p = 0.005), larger tumor size (p = 0.0004), and higher breast density (p = 0.003). Five-year EFS was 91% among younger vs. 82% among older women (p = 0.0005). In women aged < 65, there were 48 EFS events, and triple negative patients had significantly worse EFS compared to other subtypes (p = 0.003). Smokers also had worse EFS (p = 0.04). In women aged ≥ 65, there were 26 events, and both tumor size (p = 0.02) and mastectomy (p = 0.03) were significant for EFS. Conclusions: In our sample, triple negative subtype, smoking history, tumor size, and surgery type were significantly associated with shorter EFS. Race, BMI, alcohol use, parity, breast density, radiation treatment, and specific chemotherapy regimen were not significant for EFS in either age group. Full article

Triple-negative breast cancer (TNBC) remains a major therapeutic challenge due to pronounced molecular heterogeneity, transcriptional plasticity, and frequent treatment resistance. MicroRNA (miRNA)-based strategies have emerged as potential approaches for modulating dysregulated gene expression networks in TNBC; however, the contribution of understudied miRNA families to TNBC-associated regulatory programs remains incompletely understood. This study aimed to investigate the tumor-suppressive role of miR-548f-3p in TNBC and to identify candidate downstream effectors, with particular focus on ANP32E. An integrative analysis combining public transcriptomic datasets, clinical expression profiling, computational target prediction, network-based prioritization, pathway analysis, and single-cell transcriptomic assessment identified miR-548f-3p as consistently downregulated in TNBC. Among candidate downstream targets, ANP32E, a chromatin-associated regulator involved in H2A.Z histone variant dynamics, was identified as a potential effector exhibiting increased expression in TNBC and enrichment within malignant epithelial cell populations. An inverse association between miR-548f-3p and ANP32E expression was observed in patient-derived samples. In breast cancer cell models, miR-548f-3p mimic restoration increased apoptosis, promoted G₀/G₁ accumulation, and reduced migration- and invasion-associated readouts, although measurable effects were also observed in non-tumorigenic MCF-10A cells. These phenotypic changes were accompanied by reduced ANP32E expression at the protein level, indicating that ANP32E expression is responsive to miR-548f-3p restoration. This study supports miR-548f-3p as a candidate tumor-suppressive miRNA in TNBC. The reduction in ANP32E protein expression following miR-548f-3p restoration, together with computational, single-cell, and clinical expression evidence, supports ANP32E as an expression-responsive candidate downstream effector of miR-548f-3p. Further reporter-based and rescue experiments are required to confirm direct 3′UTR-mediated targeting and to define the mechanistic contribution of ANP32E within the broader miR-548f-3p regulatory network. Full article

Background: Triple-negative breast cancer (TNBC) lacks effective targeted therapies, and its dependence on glycolysis represents a potential metabolic vulnerability. EIF3H, the largest subunit of the eukaryotic translation initiation factor 3 complex and a putative deubiquitinase, has been implicated in tumor progression, but its role in TNBC metabolism remains unclear. Methods: EIF3H expression and prognostic value were evaluated in public datasets, clinical TNBC specimens, and cell lines. Functional roles were examined using proliferation, colony formation, migration, and xenograft assays. Mechanisms were investigated by mass spectrometry, co-immunoprecipitation, ubiquitination and glycolytic rate assays, macrophage co-culture, and single-cell transcriptomic analysis. Results: EIF3H was significantly upregulated in TNBC and associated with poor survival. Transcriptionally activated by TRPS1, EIF3H bound to lactate dehydrogenase A (LDHA), reduced its ubiquitination, and prevented its proteasomal degradation. LDHA stabilization enhanced glycolysis and lactate production, thereby promoting TNBC cell proliferation and migration in vitro and tumor growth in vivo; these effects were abolished by LDHA knockdown and restored by LDHA re-expression. In addition, tumor-derived lactate induced M2 macrophage polarization via GPR65, which in turn reinforced malignant progression. Conclusions: Our findings define a TRPS1–EIF3H–LDHA axis that drives glycolysis-dependent TNBC progression and reveal lactate–GPR65 signaling as a mediator of tumor–macrophage crosstalk, supporting EIF3H as a potential prognostic biomarker and therapeutic target in TNBC. Full article

Background/Objectives: The health-protective properties of olive oil phenolics, including their potential chemopreventive and anticancer effects, have attracted considerable scientific interest. However, their in vivo efficacy and mechanisms of action remain insufficiently understood. Recent advances in extraction and purification technologies have enabled large-scale production of highly purified olive oil phenols and phenolic-rich extracts, facilitating translational research. Methods: Herein, the antitumor efficacy of isolated olive oil phenols and phenolic-rich formulations was investigated in an MDA-MB-231 triple-negative breast cancer (TNBC) xenograft model. Results: Intraperitoneal administration of oleocanthal (OLC), oleuropein aglycone (OleA) or their combination reduced endpoint tumor burden, with OLC exhibiting the most pronounced effect. Oral administration of total olive oil phenolics (OOPs) achieved comparable efficacy. Pre-treatment initiated before tumor cell implantation conferred the greatest protection, consistent with a prophylactic mode of action. In contrast, delayed intervention displayed diminished or no antitumor benefit. Phenolic-rich extra virgin olive oil likewise showed an inhibition trend in tumor progression. Mechanistically, OOPs attenuated plasma protein oxidation, modulated proteasome mediated proteolysis, and reduced γH2AX levels in vivo. Furthermore, OOPs negatively affected the MDA-MB-231 cell migration in a concentration-dependent manner in vitro. Conclusions: Collectively, these findings are consistent with antitumor activities of olive oil phenolics via multiple mechanisms and support their further investigation as prophylactic agents in TNBC and as nutraceuticals. Full article

Background/Objectives: The inflammatory burden index (IBI), calculated as C-reactive protein (CRP) multiplied by the neutrophil-to-lymphocyte ratio (NLR), has demonstrated prognostic value across several solid tumors. Its role in breast cancer, however, has not been investigated. This study evaluated whether pretreatment or post-treatment IBI could predict pathological complete response (pCR) in patients with HER2-positive or triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy (NAC). Methods: This single-center retrospective study included 61 patients who completed NAC followed by surgery between 2019 and 2025. IBI was calculated before and after NAC, and the treatment-related change (ΔIBI) was assessed. Conventional inflammatory indices, including NLR, platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), C-reactive protein-to-albumin ratio (CAR), and absolute lymphocyte count (ALC), were evaluated for comparison. Analyses included Mann–Whitney U tests, paired Wilcoxon signed-rank tests, receiver operating characteristic (ROC) curve analysis, and multivariable logistic regression. Results: Twenty-nine patients (47.5%) achieved pCR. No pretreatment or post-treatment inflammatory index was significantly associated with pCR. In paired within-patient analysis, IBI increased significantly during treatment only in patients achieving pCR (p = 0.036), while remaining unchanged in the non-pCR group (p = 0.627). CAR showed an identical pattern, increasing exclusively in the pCR group (p = 0.013). This selective rise was not observed for any index lacking a CRP component and was independent of molecular subtype, anti-HER2 therapy, and chemotherapy regimen. On ROC analysis, ΔCAR yielded the highest area under the curve (AUC) among all inflammatory indices (0.637; p = 0.067), followed by ΔIBI (0.606; p = 0.157); neither reached statistical significance. Ki-67 was the only independent predictor of pCR (AUC 0.724; p = 0.003; optimal cutoff ≥25%). Conclusions: This is the first study to evaluate IBI in HER2-positive and TNBC receiving NAC. Static IBI values did not predict pCR. The selective rise in IBI and CAR during treatment in patients achieving pCR—two independently formulated CRP-based indices showing an identical pattern—suggests that the CRP component carries the biologically relevant signal. This hypothesis-generating observation warrants prospective validation in larger cohorts. Full article

Background: The growing awareness of breast cancer’s molecular diversity has not changed the technical foundations of surgery itself, but it has profoundly reshaped how surgeons think about surgery. Rather than molecular biology prescribing specific surgery, it is the surgeon’s interpretation of biological behavior—tumor subtype, genomic risk, treatment responsiveness—that influences surgical timing, extent, and feasibility. This is particularly important in the developing world, where mastectomy continues to be the default surgery, not always because it is required, but because biological nuance is underutilized in surgical planning. This review integrates existing evidence, guidelines, and real-world clinical experience to show how a surgeon who understands tumor biology can meaningfully expand safe breast conservation, de-escalate axillary surgery, and align operative choices with systemic therapy. In essence, molecular biology becomes a lens through which surgeons can practice more personalized, precise, and less invasive surgery, without compromising oncologic safety. Recent findings: We present evidence-based algorithms focusing on Luminal A, Luminal B, HER2-positive, and triple-negative subtypes, while discussing the nuances of multifocal and multicentric disease, metaplastic histologies, and discordant lesion management. The review addresses axillary management in the molecular era, specifying the appropriateness of sentinel lymph node biopsy, targeted axillary dissection, or completion axillary dissection, and how subtype-specific nodal responses to neoadjuvant therapy can guide de-escalation strategies. Through clinical vignettes, we exemplify how molecular integration into surgical planning can modify clinical courses, enabling oncoplastic conservation in downstaged tumors and justifying definitive resection in chemo-resistant cases. We examine the implications of germline and somatic genetic testing on surgical decision-making, particularly in relation to BRCA1/2 and PALB2 mutation carriers, alongside ethical and practical counseling considerations. Additionally, we review emerging biomarkers—such as circulating tumor DNA and immune and radiomic signatures—and propose research priorities for their incorporation into surgical trials. Conclusions: Effective implementation necessitates enhanced surgeon education, standardized assays, and multidisciplinary coordination to promote equitable access, consistent utilization of biology-driven algorithms, and rigorous quality oversight. This review furnishes breast surgeons with a pragmatic framework for translating molecular knowledge into multidisciplinary, patient-centered care pathways that optimize oncological safety, aesthetic outcomes, and overall quality of life. Full article