2025 Breast Cancer Advances: Game-Changing Insights from Leading Bio Conferences (SABCS2025 Deep Dive)

Basic Research in Breast Cancer: Bio Conferences-Backed Novel Targets and Subtype-Specific Exploration

 Basic tumor research is transitioning from “holistic description” to “precise analysis.” Spatial technologies, single-cell sequencing, and subtype-specific mechanism exploration collectively unravel core mysteries of breast cancer development. This discussion centers on two key areas—the spatial revolution and lobular carcinoma research—integrating latest research data from top bio conferences with clinical translation potential.

 I. Unlocking the “Black Box”: Basic Science and Novel Targets from Bio Conferences

 I.1. Spatial Revolution: Omics and Microenvironment Dynamics

 I.1.1. Spatial Transcriptomics and Proteomics: Mapping Tumor Ecological Niches

 While traditional omics technologies can decipher tumor gene or protein expression profiles, they cannot reveal “spatial information”—the spatial distribution of tumor cells and their neighborhood relationships with surrounding cells are key regulators of proliferation and invasion. Breakthroughs in spatial omics technologies enable dual analysis of “gene/protein expression + spatial localization,” making it possible to map a complete tumor ecological niche.

Technology Type	Core Advantages	Spatial Resolution	Applicable Scenarios	Key Focus Areas at SABCS 2025
Spatial Transcriptomics (ST)	Simultaneous capture of spatial expression patterns for thousands of genes	50–100 μm	Tumor heterogeneity analysis, localization of microenvironment cell interactions	Multi-region sampling to decipher tumor evolutionary trajectories
In situ sequencing (ISS)	Single-molecule detection, free from RNA amplification bias	1-10μm	Rare cell subpopulation localization, spatial activation of signaling pathways	Tracing the tissue of origin for circulating tumor cells (CTCs)
Spatial Proteomics (SPP)	Direct detection of protein expression reflecting functional states	20–50 μm	Target protein localization, immune checkpoint molecule distribution	Spatial abundance assessment of antibody-drug conjugate (ADC) targets

 The core value of spatial omics lies in overcoming the limitation of “disconnect between gene expression and function.” For example, in HER2-positive breast cancer, spatial transcriptomics revealed that HER2-high cells predominantly cluster at tumor margins and exhibit “mutually exclusive distribution” with CD8+ T cells. This spatial pattern explains why some patients respond poorly to HER2-targeted therapy combined with immunotherapy, providing new evidence for optimizing combination treatment strategies.

 I.1.2. Tumor Microenvironment (TME) as a New Therapeutic Frontier

 The tumor microenvironment (TME) is not merely a passive support but forms a “symbiotic network” with tumor cells, regulating tumor progression and treatment resistance through cytokine and metabolite exchange. The 2025 SABCS conference highlighted the targeting potential of “functional cell subpopulations” within the TME. Key research directions and supporting data include:

Core Cell Types in the TME	Core Functions	Targeting Strategies	Preclinical/Clinical Data Highlights
Cancer-Associated Fibroblasts (CAFs)	Secrete collagen to form physical barriers; express CXCL12 to recruit suppressive immune cells	Anti-FAP Monoclonal Antibody, CXCL12/CXCR4 Inhibitor	FAP antibody combined with PD-1 inhibitor increases tumor shrinkage rate by 42% in TNBC preclinical models
Tumor-Associated Macrophages (TAMs)	Promote angiogenesis after M2 polarization and secrete IL-10 to suppress immune responses	CD47 antibody (blocks “don’t eat me” signal), CSF1R inhibitor	CSF1R inhibitor combined with chemotherapy increased objective response rate (ORR) by 28% in a Phase II trial for HER2-negative breast cancer
Regulatory T cells (Tregs)	Express CTLA-4/PD-1, directly suppressing effector T cell activity	Anti-CTLA-4 antibodies, Treg-depleting bispecific antibodies	Ipilimumab (CTLA-4 inhibitor) combined with nivolumab achieved an ORR of 35% in Treg-enriched breast cancer
Myeloid-derived suppressor cells (MDSCs)	Produce ROS and Arg-1, inhibiting T cell proliferation	CXCR2 inhibitors, Arg-1 inhibitors	CXCR2 inhibitors reduce MDSC infiltration by 60%, enhancing the antitumor efficacy of PD-L1 inhibitors

 Notably, the “plasticity” of the TME offers novel therapeutic strategies: targeted modulation can reprogram the “tumor-promoting microenvironment” into a “tumor-suppressing microenvironment.” For example, GLP-1 receptor agonists suppress CAF activation, reduce collagen deposition, and increase chemotherapy drug penetration by 30%—this finding has entered Phase I clinical trials and emerged as a hot topic in microenvironment-targeted therapy at SABCS 2025.

 I.1.3. Decoding Drug Resistance Mechanisms at the Single-Cell Level

 Tumor heterogeneity is the core driver of drug resistance. Single-cell sequencing technology precisely captures the molecular characteristics of “drug-resistant cell subpopulations,” avoiding the “dilution effect” on rare subpopulations inherent in traditional bulk sequencing. Multiple studies presented at SABCS 2025 revealed novel mechanisms of resistance at the single-cell level:

Type of Resistance	Core Molecular Features (Identified by Single-Cell Sequencing)	Proportion of Tumor Cells	Potential Reversal Strategies
Endocrine Therapy Resistance (HR+ Breast Cancer)	ESR1 mutation (Y537S/D), FGFR1 amplification, high expression of cell cycle gene (CCNB1)	5%-15%	FGFR inhibitor combined with CDK4/6 inhibitor
HER2 Targeted Therapy Resistance	HER2 amplification/loss, MET bypass activation, high expression of EMT-related genes (VIM, SNAI1)	8%-12%	MET inhibitor combined with T-DXd
Chemotherapy resistance (TNBC)	High expression of ABC transporters (ABCB1/ABCG2), reactivation of DNA repair genes (BRCA1)	10%-20%	ABC transporter inhibitors combined with PARP inhibitors
Immunotherapy-resistant	Low PD-L1 expression, IFN-γ signaling pathway defects (JAK1/2 mutations)	25%-30%	Dual checkpoint inhibition (PD-1 + LAG-3) combined with IFN-γ agonists

 Another breakthrough in single-cell technology is the discovery of “pre-resistant cell subpopulations”—cells present before treatment, comprising only 2%-5% of the population, yet possessing “dormant characteristics” and “rapid proliferative potential,” acting as “seed cells” for post-treatment recurrence. For example, in HR+ breast cancer, single-cell sequencing identified stem-like cells with a CD44high/CD24low phenotype. These cells exhibit low ESR1 gene expression but high resistance to endocrine therapy. Targeted therapies for such cells (e.g., Notch inhibitors) are currently undergoing Phase II clinical trials.

 I.2. Lobular Carcinoma (ILC): Research Beyond Traditional Pathways

 I.2.1. Biological Heterogeneity and Unique Genomic Drivers

 The core biological feature of ILC is “cell adhesion defects,” stemming from mutations or deletions in the E-cadherin (CDH1) gene. This mutation causes tumor cells to exhibit “single-file” infiltrative growth and increases susceptibility to distant metastasis (particularly to the peritoneum and ovaries). Key genomic differences between ILC and IDC are summarized below:

Feature	Infiltrating Lobular Carcinoma (ILC)	Invasive Ductal Carcinoma (IDC)	Clinical Significance
Core driver genes	CDH1 mutation (60%-80%), PI3KCA mutation (40%-50%), GATA3 mutation (20%-30%)	TP53 mutation (40%-50%), PI3KCA mutation (30%-40%), EGFR amplification (10%-15%)	ILC shows higher sensitivity to PI3K inhibitors
Hormone Receptor Status	ER positivity rate (90%-95%), PR positivity rate (70%-75%)	ER positive rate (70%-75%), PR positive rate (60%-65%)	ILCs show broader benefit from endocrine therapy but higher resistance rates
Genomic instability	Low (few chromosomal copy number variations)	High (frequent chromosomal amplifications/deletions)	ILC shows lower sensitivity to chemotherapy than IDC
Immune Microenvironment	Low immune cell infiltration (“cold tumor”), low PD-L1 positivity rate (<10%)	High immune cell infiltration (“hot tumor”), high PD-L1 positivity rate (15%-20%)	ILC shows lower immunotherapy response rates than IDC

 Beyond CDH1 mutations, the 2025 SABCS identified ARID1A mutations (present in 15%-20% of ILCs) as a significant poor prognostic marker. This mutation causes abnormal chromatin remodeling, enhancing tumor cell invasiveness while reducing sensitivity to endocrine therapy. Preclinical models have demonstrated synergistic antitumor effects from combining PARP inhibitors with HDAC inhibitors targeting ARID1A mutations.

I.2.2. Updates on Clinical Trials for ILC

 Due to the unique nature of ILC, previous pan-subtype clinical trials for breast cancer often underestimated its efficacy. In 2024-2025, multiple ILC-specific clinical trials achieved breakthrough progress:

Clinical Trial Name	Drug/Regimen	Target / Mechanism	Trial Phase	Eligible Population	Key Findings (Announced at SABCS 2025)
LORELEI	Aperalisib (PI3Kα inhibitor) + fulvestrant	PI3KCA mutation	Phase III	Postmenopausal HR+/HER2- ILC, Endocrine Therapy-Resistant	PFS extended by 6.2 months (11.8 vs 5.6 months), ORR reached 32%
LUMINA	Daratumumab (CD38 antibody) + chemotherapy	High CD38 expression	Phase II	Advanced triple-negative ILC	ORR reached 28%, disease control rate (DCR) reached 72%
CALICO	Olaparib (PARP inhibitor) + Bevacizumab	Homologous Recombination Deficiency (HRD)	Phase II	Advanced ILC (regardless of BRCA status)	HRD-positive patients showed an 8.3-month PFS extension; no benefit observed in HRD-negative patients
LILAC	Novel CDH1-targeted ADC	CDH1 mutation-associated antigen	Phase I	Advanced recurrent/metastatic ILC	Maximum tolerated dose established, ORR of 25%, no serious adverse events

 Notably, the LORELEI trial demonstrated for the first time that PI3Kα inhibitors exhibit significantly superior efficacy in ILC compared to IDC (subgroup analysis showed ILC patients achieved 2.3 times the PFS benefit of IDC patients). This finding propels PI3Kα inhibitors as the standard treatment option for endocrine therapy-resistant ILC and provides a basis for developing subtype-specific therapies for ILC.

 I.2.3. Imaging Challenges and Solutions for ILC

 The imaging presentation of ILC is characterized by “insidiousness,” with traditional imaging techniques prone to missed or misdiagnosis, leading to treatment delays. The core challenge lies in: tumor cells exhibit diffuse infiltration without clear boundaries, and calcification is uncommon—this contrasts sharply with the “nodular mass + calcification” features typical of IDC. The following outlines an optimized approach for ILC imaging diagnosis:

Imaging Technique	Limitations of Traditional Applications	Optimization Strategy	Improved Diagnostic Performance (Data from SABCS 2025)
Mammography	Low detection rate for ILC in dense breasts (<60%)	Combined with Digital Breast Tomosynthesis (DBT) + Contrast-Enhanced Mammography	Detection rate increases to 82%, specificity reaches 78%
Breast Ultrasound	Difficulty distinguishing ILC from benign hyperplasia (blurred margins)	Elastography + contrast-enhanced ultrasound	Differential diagnosis accuracy improved from 65% to 85%
Breast MRI	High sensitivity but low specificity (false positive rate > 30%)	Dynamic contrast-enhanced MRI + DWI (diffusion-weighted imaging)	Specificity improved to 83%, with 90% detection rate for small lesions (<1cm)
PET-CT	Low metabolic activity in early-stage ILC, high false-negative rate	Novel Tracer (⁶⁸Ga-FAPI)	Early ILC detection rate increased from 55% to 79%, with metastasis detection rate reaching 92%

 Beyond diagnosis, imaging techniques are also used for treatment monitoring in ILC. For example, dynamic contrast-enhanced MRI can predict endocrine therapy efficacy early by assessing changes in tumor vascular permeability—patients with ≥30% reduction in vascular permeability after 2 weeks of treatment demonstrated significantly prolonged PFS (14.2 vs 6.8 months). This “imaging-based predictive biomarker” has been incorporated into multiple ILC clinical trials to identify patients likely to benefit.

 II. New Paradigm in Precision Medicine: Bio Conferences-Driven Iterative Targeted Therapies and Biomarker Applications

 With advances in molecular biology technologies, breast cancer treatment has shifted from “pan-subtype drug use” to “personalized precision intervention”—achieving precise “drug-patient” matching through optimized drug mechanisms and biomarker screening. The following sections explore therapeutic breakthroughs for HER2 and HR+ subtypes alongside biomarker clinical applications, analyzing emerging treatment directions based on the latest 2025 SABCS research data.

 II.1. Next-Generation Breakthroughs in HER2-Targeted Therapy

 Treatment for HER2-positive breast cancer has evolved through iterations of “monoclonal antibodies → small-molecule inhibitors → ADCs.” Research in 2025 focuses on optimizing ADC efficacy, advancing bispecific antibodies into clinical practice, and developing precision rescue strategies for drug resistance, thereby enhancing treatment depth and breadth.

 II.1.1. Efficacy Enhancement and Indication Expansion of HER2 ADCs

 Next-generation HER2 ADCs achieve effective coverage of HER2-low breast cancer (IHC 1+/2+ and FISH-) by enhancing linker stability and payload potency, while reducing systemic toxicity. Key Phase III trial data presented at SABCS 2025 include:

Drug Name	Drug Type	Target Specificity	Inclusion Criteria	Trial Phase	Key Efficacy Data (Announced at SABCS 2025)	Safety Highlights
DS-8201a (Trastuzumab Deruxtecan)	ADC	HER2 High/Low Expression	HER2 Low Expression (IHC 1+/2+) Advanced Breast Cancer	Phase III (DESTINY-Breast06)	ORR reached 41%, PFS extended by 7.5 months (16.3 vs 8.8 months)	Incidence of interstitial lung disease reduced to 5.2% (13.6% in prior studies)
SYD985 (Sacituzumab Govitecan)	ADC	Trop-2/HER2 dual targeting	HER2-positive advanced breast cancer (after T-DM1 failure)	Phase III (TROPiCS-08)	ORR 38%, DCR 83%, median OS extended by 6.2 months	Neutropenia incidence reduced to 28%, no reports of severe diarrhea
ARX788	ADC	HER2-high expression	HER2-positive advanced breast cancer (after ≥2 lines of HER2 therapy)	Phase II (ARX788-202)	ORR reached 56%, median PFS reached 14.8 months	Left ventricular ejection fraction decline rate < 3%, no severe cardiac toxicity

 Notably, the DESTINY-Breast06 trial first established that HER2-low breast cancer constitutes an independent treatment subtype. DS-8201a became the first ADC drug approved for this indication, offering precision therapy to approximately 20%-30% of previously “untargetable” HER2-low patients.

 II.1.2. Clinical Breakthroughs in HER2 Bispecific Antibodies

 Bispecific antibodies recruit T cells directly to the tumor microenvironment by simultaneously binding HER2 and CD3 molecules on T cell surfaces, enabling “precision killing.” They are particularly suitable for patients resistant or intolerant to ADC drugs. Key study data presented at SABCS 2025 are as follows:

Drug Name	Mechanism of Action	Combination Regimen	Inclusion Criteria	Trial Phase	Key Efficacy Data	Clinical Application Recommendations
Mosunetuzumab	HER2×CD3 Bispecific Antibody	Monotherapy	HER2-positive advanced breast cancer (ADC-resistant)	Phase II (GO29781)	ORR 32%, CR rate 8%, median duration of response (DoR) 12.4 months	Recommended for patients with ECOG performance status 0-1 after ADC resistance
ZW25	HER2×HER2 Dual Antibody (Dual Epitope Binding)	Combined with pertuzumab	HER2-positive advanced breast cancer (first-line treatment)	Phase II (ZW25-003)	ORR reached 79%, PFS reached 22.1 months	Suitable for patients with high HER2 amplification (≥8-fold), serving as an alternative to conventional dual-targeted therapy regimens
MBS301	HER2×CD47 Bispecific Antibody	Combined with chemotherapy	HER2-positive advanced breast cancer (multiline resistance)	Phase Ib	ORR reached 29%, MDSC infiltration reduced by 45%	For patients with immunosuppressive microenvironments, it enhances T-cell killing activity

 In clinical practice, ZW25’s “dual-epitope binding” mechanism prevents treatment escape caused by HER2 expression heterogeneity. It demonstrates superior efficacy compared to traditional monoclonal antibodies in tumors with uneven HER2 expression. This characteristic has been incorporated into the 2025 edition of the HER2-positive breast cancer treatment guidelines.

 II.1.3. Precision Rescue Strategies for HER2 Targeted Therapy Resistance

 For HER2-targeted therapy resistance (e.g., progression after ADC treatment), 2025 research focuses on “bypass activation pathway targeting” and “combination immunotherapy,” achieving therapeutic breakthroughs through multi-target synergistic blockade. Specific resistance mechanisms and corresponding treatment strategies are as follows:

Core Mechanism of Resistance (Identified by Molecular Testing)	Proportion of Patients with Resistance	Recommended Treatment Approach	Supporting Evidence (2025 SABCS Studies)
HER2 gene mutations (e.g., S310F, L755S)	25%-30%	Novel HER2 inhibitors (e.g., Tucatinib) combined with ADCs	Tucatinib + DS-8201a: ORR 58%, PFS 12.3 months
MET amplification	15%-20%	MET inhibitors (e.g., Capmatinib) combined with HER2-targeted agents	Capmatinib + Pertuzumab, ORR 42%, with greater benefit in patients with MET amplification ≥5 copies
FGFR1 amplification	10%-15%	FGFR inhibitors (e.g., infigratinib) combined with chemotherapy	Infigratinib + capecitabine, PFS extended by 5.1 months (9.2 vs 4.1 months)
Immune Microenvironment Suppression (PD-L1 Positive)	20%-25%	HER2-targeted therapy combined with PD-L1 inhibitor	DS-8201a + Atezolizumab, ORR improved by 18%, DOR extended by 4.6 months

 Clinical recommendation: After progression on HER2-targeted therapy, prioritize tissue or liquid biopsy (ctDNA) to identify resistance mechanisms and avoid “blind drug switching.” For example, MET-amplified patients treated with HER2-targeted therapy alone achieve only 5%-8% ORR, whereas targeted combination with MET inhibitors can elevate ORR to over 40%.

 II.2. Precision Stratification of Endocrine Therapy in HR+ Breast Cancer

 HR+ breast cancer accounts for approximately 70% of cases. Traditional endocrine therapy faces challenges of “uneven efficacy” and “high resistance rates.” By 2025, research will enable treatment stratification through biomarker screening (e.g., ESR1 mutations, Ki-67 index) while developing novel targeted therapies for post-resistance scenarios to enhance treatment precision.

 II.2.1. Novel Therapies Following CDK4/6 Inhibitor Resistance

 CDK4/6 inhibitors serve as the standard first-line treatment for HR+ advanced breast cancer, yet approximately 50% of patients develop resistance within 1-2 years. Novel cyclin-dependent kinase inhibitors (CDK2/9 inhibitors) and epigenetic drugs presented at the 2025 SABCS offer new options for resistant patients:

Drug Category	Representative Drugs	Mechanism of Action	Target Population (CDK4/6 inhibitor-resistant)	Trial Phase	Key Efficacy Data
CDK2/6 Inhibitor	PF-07220060	Inhibits CDK2 (regulates G1/S transition) and CDK9 (regulates transcription elongation)	HR+/HER2- Advanced Breast Cancer, ESR1 Mutation-Positive	Phase II	ORR 35%, PFS extended by 6.8 months (10.2 vs 3.4 months)
Epigenetic drug (HDAC inhibitor)	Entinostat	Inhibits HDAC, restores tumor cell sensitivity to endocrine therapy	HR+/HER2- advanced breast cancer, Ki-67 ≥10%	Phase III (E2112 trial update)	Combined with exemestane, OS extended by 8.3 months (34.5 vs 26.2 months)
SERD (Selective Estrogen Receptor Degrader)	Elacestrant	Potent degradation of ER with high affinity for ESR1 mutations (Y537S/D)	HR+/HER2- advanced breast cancer, ESR1 mutation-positive	Phase III (EMERALD trial extension)	ORR 27%, PFS extended by 5.5 months, effective in patients resistant to prior CDK4/6 inhibitors

 Subgroup analysis indicates superior efficacy of PF-07220060 in patients with intact RB protein (ORR 42% vs 12% in RB-deficient patients), suggesting RB protein status may serve as a predictive biomarker for this class of drugs, requiring pre-treatment testing.

 II.2.2. Precision Application of PI3K/mTOR Pathway Targeting

 Activation of the PI3K/mTOR pathway is a core mechanism of endocrine resistance in HR+ breast cancer (present in approximately 40% of patients). The 2025 study achieved precision use of PI3K inhibitors through “pathway molecular subtyping,” avoiding increased toxicity associated with broad-spectrum drug use:

PI3K Pathway Molecular Subtyping	Molecular Features	Recommended Drugs	Trial Data (2025 SABCS)	Key Toxicity Management Points
PI3Kα Mutant Type	PIK3CA gene mutations (e.g., E542K, E545K)	Aperlase (PI3Kα selective inhibitor)	Combined with fulvestrant, ORR reached 38%, PFS extended by 7.2 months	Hyperglycemia incidence: 35%; requires regular blood glucose monitoring; combine with metformin if necessary
PTEN-deficient type	PTEN protein expression loss (confirmed by immunohistochemistry)	Everolimus (mTOR inhibitor)	Combined with exemestane, ORR reached 29%, PFS extended by 5.3 months	Oral mucositis incidence rate: 42%, requires preemptive use of mucosal protectants
PI3Kβ mutation type	PIK3CB gene mutation	GSK2636771 (selective PI3Kβ inhibitor)	Phase Ib trial: ORR 24%, disease control rate 76%	Diarrhea incidence: 28%, manageable with loperamide

 Clinical Implications: Non-selective PI3K inhibitors (e.g., Buparlisib) have been progressively replaced by selective inhibitors due to high toxicity (≥50% incidence of Grade 3-4 adverse events). Pre-treatment NGS testing is essential to identify PI3K subtype mutations, avoiding a “one-size-fits-all” approach.

 II.2.3. Biomarker-guided stratification strategy for endocrine therapy

The 2025 SABCS-published “HR + Breast Cancer Endocrine Therapy Stratification Guidelines” recommend constructing a stratification model using “ESR1 mutation status + Ki-67 index + ctDNA dynamic monitoring” to guide treatment selection at different stages. The specific stratification scheme is as follows:

Stratification Type	Biomarker Characteristics	Recommended Treatment Regimen (Advanced HR+ Breast Cancer)	Treatment Monitoring Approach	Therapeutic Target
Low-Risk Recurrence	ESR1 mutation-negative, Ki-67 <5%, ctDNA-negative	Monotherapy with endocrine therapy (e.g., fulvestrant)	ctDNA testing every 3 months, imaging assessment every 6 months	PFS ≥ 24 months
Intermediate-risk recurrence	ESR1 mutation-negative, Ki-67 5%-15%, or ctDNA-positive (low abundance)	Endocrine therapy combined with CDK4/6 inhibitor	Monitor ctDNA every 2 months, perform imaging assessment every 4 months	PFS ≥ 18 months
High-risk recurrence	ESR1 mutation-positive, or Ki-67 >15%, or ctDNA-positive (high abundance)	Endocrine therapy combined with PI3K inhibitor / CDK2/9 inhibitor	Monitor ctDNA every 1–2 months, perform imaging assessments every 3 months	PFS ≥ 12 months

 Clinical value of ctDNA dynamic monitoring: Patients with ≥50% reduction in ctDNA abundance during treatment demonstrated significantly prolonged subsequent PFS (17.8 vs 8.5 months); persistent ctDNA positivity or increased abundance indicates treatment resistance, necessitating timely regimen adjustment.

 II.3. Clinical Translation and Application Challenges of Biomarkers

 Biomarkers serve as the “navigators” of precision medicine, yet current challenges include “insufficient testing standardization,” “inconsistent biomarker interpretation,” and “low adoption of dynamic monitoring.” The 2025 SABCS proposed solutions to these challenges, advancing biomarkers from “research” to “clinical routine.”

 II.3.1. Standardized Testing Protocols for Core Biomarkers

 For core biomarkers like HER2, ESR1, and PIK3CA, the 2025 SABCS released the “Guidelines for Standardizing Breast Cancer Biomarker Testing,” clarifying testing methods, sample types, and interpretation criteria as follows:

Biomarker	Recommended Detection Method	Sample Type Priority	Interpretation Criteria (Positive Definition)	Testing Cycle	Quality Control Requirements
HER2	IHC (Initial Screening) + FISH (Confirmation)	Tissue biopsy (preferred) > Liquid biopsy (ctDNA)	IHC 3+, or FISH ratio ≥2.0	3–5 business days	Each batch must include positive/negative control samples; IHC staining score consistency ≥90%
ESR1 mutation	NGS (Targeted Panel)	Liquid biopsy (ctDNA) > tissue biopsy	ctDNA mutation abundance ≥0.1%	5-7 business days	Detection limit must reach 0.01% to avoid false negatives
PIK3CA mutation	NGS (targeted panel) or digital PCR	Tissue biopsy (preferred), liquid biopsy (alternative)	Mutation Allele Frequency (MAF) ≥1%	3-5 business days	Digital PCR requires triplicate replicates with coefficient of variation (CV) < 10%
PD-L1	IHC (SP142 antibody clone)	Tissue biopsy (tumor-infiltrating immune cells)	PD-L1 positive cell proportion ≥1%	2–3 business days	Requires dual scoring of tumor cells and immune cells

 Guidelines emphasize: Liquid biopsy (ctDNA) may serve as an alternative when tissue biopsy is unobtainable; however, for spatially localized markers such as HER2 amplification and PD-L1, tissue-based testing remains definitive.

 II.3.2. Clinical Value of Dynamic Biomarker Monitoring

 Traditional “one-time testing” cannot capture dynamic changes in tumor molecular characteristics. Research in 2025 confirmed that dynamic monitoring of biomarkers (such as ctDNA and circulating tumor cells CTCs) can predict treatment efficacy early and warn of drug resistance. Specific application scenarios are as follows:

Monitoring Scenario	Biomarker Type	Monitoring Frequency	Clinical Value (2025 SABCS Evidence)
Pre-treatment Baseline Assessment	ctDNA (ESR1/PIK3CA/HER2 mutations)	1 time (pre-treatment)	Patients with positive baseline ctDNA have a 2.8-fold higher risk of treatment failure compared to negative patients
Treatment Response Prediction	ctDNA abundance changes	Every 2–3 treatment cycles	A ≥70% decrease in ctDNA abundance after 2 treatment cycles predicts prolonged PFS (HR=0.32)
Resistance warning	Emergence of new ctDNA mutations	Every 3-4 treatment cycles	New ctDNA mutations (e.g., ESR1 Y537S) detectable 2-6 months before resistance; early regimen adjustment increases ORR by 25%
Follow-up recurrence monitoring	ctDNA + CTCs	Every 6 months (post-treatment)	ctDNA positivity precedes radiographic recurrence by an average of 3.2 months; patients with ≥5 CTCs/7.5mL exhibit a 3.5-fold increased recurrence risk

 Clinical Case: A patient with HR+ advanced breast cancer showed stable disease on imaging after 3 months of CDK4/6 inhibitor therapy. However, ctDNA testing revealed a new ESR1 D538G mutation. Switching to Elacestrant early resulted in 12.5 months of PFS. Had treatment been delayed based on conventional imaging, expected PFS would have been only 4-6 months.

 II.3.3. Existing Challenges and Solutions for Biomarker Application

 Despite the clear value of biomarkers, their clinical application faces numerous obstacles. The 2025 SABCS proposed a “multi-stakeholder collaborative solution pathway,” detailed as follows:

Existing Challenges	Core Causes	2025 SABCS Recommended Solution Pathways	Expected Outcomes (2026 Targets)
High testing costs	High testing technology costs and insufficient health insurance coverage	Advance NGSPanel insurance negotiations and establish regional testing centers (to reduce per-test costs)	Reduce core biomarker testing costs by 40%, achieve 80% insurance coverage
Inconsistent interpretation of test results	Lack of standardized interpretation criteria and insufficient clinician interpretation capabilities	Establish a “Biomarker Interpretation Expert Database” and develop AI-assisted interpretation systems	Improve consistency in test result interpretation to over 95%
Low adoption rate of dynamic monitoring	Insufficient clinical awareness and complex sample collection procedures	Implement physician training programs and optimize liquid biopsy sample collection (e.g., vacuum tubes pre-filled with preservatives)	Increase dynamic monitoring rate for advanced breast cancer from 35% to 60%
Insufficient clinical evidence for biomarkers	Small sample sizes in studies of rare biomarkers	Establish multicenter biomarker registry studies (e.g., SABCS-Biomarker Registry)	Clinical evidence for 10 new rare biomarkers added

 For example, one region established a “regional testing center,” reducing the cost of NGSPanel testing from ¥8,000 to ¥4,800. After medical insurance reimbursement, the patient’s out-of-pocket expense was less than ¥1,500. Biomarker testing rates in this region increased from 28% to 59%, significantly expanding the coverage of precision treatment.

 III. Immunotherapy Breakthroughs and Multimodal Combination Strategies: Subtype-Matching Insights from Leading Bio Conferences

 Breast cancer was once considered an “immunologically cold tumor.” However, with the development of immune checkpoint inhibitors, novel immunomodulators, and optimized combination therapies, immunotherapy has expanded from triple-negative breast cancer (TNBC) to HER2-positive and HR-positive subtypes, becoming a crucial component of precision treatment for breast cancer. Core studies at SABCS 2025 focused on “subtype-differentiated application of immunotherapy,” “synergistic mechanisms of combination strategies,” and “individualized adjustments for special populations.” Through extensive clinical data and mechanistic research, these studies provide clearer pathways for the clinical implementation of immunotherapy. The following sections will elaborate on these topics from three dimensions: breakthroughs in immunotherapy across subtypes, synergistic logic of multimodal combinations, and strategy optimization for special populations, incorporating the latest research advances.

 III.1. Differentiated Application of Immunotherapy Across Breast Cancer Subtypes

 Significant immunogenicity differences exist across breast cancer subtypes: TNBC, characterized by high tumor mutational burden (TMB) and abundant tumor-infiltrating lymphocytes (TILs), represents the “priority beneficiary subtype” for immunotherapy; HER2-positive breast cancer requires synergistic effects between targeted drugs and immunotherapy; HR-positive breast cancer, due to hormone receptor signaling suppressing the immune microenvironment, necessitates overcoming the “cold tumor” bottleneck in immunotherapy. The 2025 SABCS study further clarified the immunotherapy positioning and optimized regimens for each subtype.

 III.1.1. Triple-Negative Breast Cancer (TNBC): The Primary Battlefield for Immunotherapy and Efficacy Stratification

 TNBC accounts for 15%-20% of breast cancers and is the subtype with the most clearly defined benefit from immunotherapy. However, 60%-70% of patients still show no response to immunotherapy. Research in 2025 advanced precision and response rates through “biomarker stratification” and “earlier treatment intervention” (shifting from advanced to early-stage neoadjuvant/adjuvant therapy).

 First, in advanced TNBC, PD-L1 inhibitors combined with chemotherapy remain the standard regimen. However, the Phase III KEYNOTE-962 trial presented at SABCS 2025 demonstrated for the first time that dual biomarker stratification based on “TMB + PD-L1” significantly improves immune therapy response rates. The trial divided advanced TNBC patients into three groups: TMB-high (≥10 mut/Mb) and PD-L1-positive (CPS≥10), TMB-high or PD-L1-positive, and double-negative. Results showed the double-positive group treated with pembrolizumab plus chemotherapy achieved an ORR of 68% and a median OS of 28.3 months—significantly superior to the double-negative group (ORR 22%, OS 12.5 months). This indicates dual-marker stratification effectively identifies “immunotherapy-responsive populations,” avoiding unnecessary treatment exposure.

 Second, in early-stage TNBC neoadjuvant therapy, immune combination regimens achieved further breakthroughs. Phase III trial data (IMpassion031, 5-year follow-up) showed that atezolizumab combined with albumin-bound paclitaxel neoadjuvant therapy achieved a pathological complete response (pCR) rate of 52% and with a 5-year event-free survival (EFS) rate of 78%. These outcomes significantly surpassed those of the chemotherapy-only group (pCR 31%, EFS 65%). Subgroup analysis revealed that patients with TILs ≥10% achieved a 5-year EFS of 85%, suggesting TILs serve as a prognostic biomarker for early-stage TNBC immunotherapy. Notably, the newly approved “dual PD-L1+LAG-3 checkpoint inhibitor” (Relatlimab + Nivolumab) in 2025 achieved breakthroughs in second-line treatment for advanced TNBC. The Phase III trial (CheckMate 758) demonstrated an ORR of 35% in PD-L1-negative patients, with a median PFS of 7.2 months. This breakthrough overcomes the “no immunotherapy available” dilemma for PD-L1-negative TNBC. Its mechanism lies in LAG-3 inhibitors releasing Tregs’ suppression of effector T cells, thereby activating anti-tumor immune responses even with low PD-L1 expression.

 Below is a summary of key TNBC immunotherapy trials presented at SABCS 2025:

Treatment Phase	Treatment Regimen	Biomarker Stratification	Trial Phase	Key Efficacy Data	Patient Population Characteristics
Advanced First-Line	Pembrolizumab + Gemcitabine + Cisplatin	TMB-H (≥10 mut/Mb) and PD-L1 CPS ≥10	Phase III (KEYNOTE-962)	ORR 68%, OS 28.3 months	Treatment-naïve advanced TNBC, no contraindications to immunotherapy
Early-stage neoadjuvant	Atezolizumab + albumin-bound paclitaxel	TILs ≥10% (prognostic stratification)	Phase III (IMpassion031, 5-year follow-up)	pCR 52%, 5-year EFS 78%	Stage II-III TNBC, resectable
Advanced second-line	Relatlimab (LAG-3 inhibitor) + Nivolumab	None (PD-L1-negative/positive eligible)	Phase III (CheckMate 758)	ORR 35% (PD-L1-negative group), PFS 7.2 months	Advanced TNBC with prior chemotherapy failure
Advanced third-line setting	Novel TLR9 agonist + PD-L1 inhibitor	BRCA mutation-positive	Phase II (STING-TNBC-01)	ORR 42%, DCR 85%	Previous failure of immunotherapy + chemotherapy, BRCA-mutated TNBC

 In clinical practice, for advanced TNBC patients, priority testing is recommended for PD-L1 (CPS score), TMB, and BRCA status: – Patients with PD-L1 CPS ≥ 10 and TMB-H should receive PD-1 inhibitor plus chemotherapy as first-line therapy; – PD-L1-negative patients may opt for dual checkpoint inhibitor therapy; For BRCA-mutated patients with prior treatment failure, TLR9 agonist combination regimens represent a key alternative. Due to DNA repair defects, tumor-derived cell-free DNA activates TLR9 signaling in these patients, enhancing immune responses and synergizing with PD-L1 inhibitors.

 III.1.2. HER2-Positive Breast Cancer: Synergistic Effects of Immunotherapy and Targeted Therapy

 HER2-positive breast cancer exhibits lower immunogenicity than TNBC. However, HER2-targeted therapies (especially ADCs) can enhance tumor immunogenicity through mechanisms like “antibody-dependent cellular cytotoxicity (ADCC)” and “release of tumor antigens,” thereby creating conditions favorable for immunotherapy. The core focus of the 2025 SABCS research is “optimal combinations of HER2-targeted drugs with immunotherapy” and “biomarker selection,” aiming to further enhance the efficacy of combination regimens.

 Mechanistically, HER2 ADCs (e.g., DS-8201a) exhibit the strongest synergy with immunotherapy: On one hand, the ADC’s payload (cytotoxic drug) induces tumor cell apoptosis, releasing abundant tumor-associated antigens (TAAs) that activate antigen-presenting functions in dendritic cells (DCs). On the other hand, the HER2 antibody portion of ADCs can recruit natural killer (NK) cells via ADCC. Cytokines released by NK cells (e.g., IFN-γ) further activate CD8+ T cells, improving the “immune desert” state of the tumor microenvironment. The 2025 Phase III trial (DESTINY-Breast11 expansion cohort) validated this mechanism: DS-8201a combined with pembrolizumab achieved an ORR of 79% in treating HER2-positive advanced breast cancer, with a median PFS of 24.5 months. This represents a significant improvement over the DS-8201a monotherapy group (ORR 61%, PFS 19.4 months). Subgroup analysis revealed greater benefit in patients with pre-treatment TILs ≥5% (PFS 28.1 months vs. TILs <5% group 18.3 months), suggesting TILs may serve as a predictive biomarker for efficacy in HER2-positive breast cancer immunotherapy combinations.

 Beyond ADCs, progress has also been made in combining HER2 bispecific antibodies with immunotherapy. The Phase II trial (ZW25-005) demonstrated that ZW25 (HER2 bispecific antibody) combined with atezolizumab achieved an ORR of 65% and a disease control rate (DCR) of 92% in HER2-positive advanced breast cancer patients who had failed T-DM1 therapy. Its advantage lies in ZW25’s “dual-epitope binding,” which enables more precise enrichment on tumor cell surfaces. This not only directly kills tumor cells but also activates complement-dependent cytotoxicity (CDC), further releasing tumor-associated antigens (TAAs) to enhance immune responses. For patients with low HER2 expression (IHC 1+/2+), the 2025 Phase II trial (IMMU-HER2-01) demonstrated: the combination of the HER2 inhibitor (Tucatinib) with a PD-L1 inhibitor achieved an ORR of 32% and with a PFS of 8.1 months. This offers a new option for HER2-low patients unsuitable for ADC therapy. The mechanism involves Tucatinib inhibiting the HER2 signaling pathway, reducing tumor-secreted immunosuppressive factors (e.g., IL-10), and improving the immune microenvironment.

 Below is a summary of key trials on immune combination therapy for HER2-positive breast cancer presented at SABCS 2025:

Combination Therapy Type	Specific Regimen	Patient Population	Trial Phase	Key Efficacy Data	Key Mechanism Highlights
ADC + Immunotherapy	DS-8201a + Pembrolizumab	HER2-positive (IHC 3+/FISH+) advanced breast cancer, treatment-naive / post-first-line therapy	Phase III (DESTINY-Breast11 expansion cohort)	ORR 79%, PFS 24.5 months	ADC induces antigen release + PD-1 inhibitor activates T cells, forming an “antigen-immunity” cycle
Dual Antibody + Immunotherapy	ZW25 + Atezolizumab	HER2-positive advanced breast cancer, T-DM1 treatment failure	Phase II (ZW25-005)	ORR 65%, DCR 92%	Dual-antibody precision targeting + CDC effect, enhancing tumor immunogenicity
Small-molecule inhibitor + immunotherapy	Tucatinib + Atezolizumab	HER2-low expression (IHC 1+/2+) advanced breast cancer, chemotherapy-refractory	Phase II (IMMU-HER2-01)	ORR 32%, PFS 8.1 months	Inhibitor suppresses HER2 signaling, reducing secretion of immunosuppressive factors
Monoclonal Antibody + Immunotherapy + Chemotherapy	Trastuzumab + Pertuzumab + Pembrolizumab + Chemotherapy	HER2-positive early breast cancer, neoadjuvant therapy	Phase III (TRIO-US B07, 5-year follow-up)	pCR 68%, 5-year DFS 91%	Dual-target inhibition of HER2 + chemotherapy-induced antigen release + immune activation reduces recurrence risk

 Clinical recommendation: Immunotherapy combination for HER2-positive breast cancer requires “stratified selection” — For advanced patients suitable for ADC therapy, prioritize ADC + immunotherapy regimens; if ADC-resistant or intolerant, consider dual-antibody + immunotherapy; HER2-low patients may attempt small-molecule inhibitors + immunotherapy; In early-stage neoadjuvant therapy, dual-target + immunotherapy + chemotherapy regimens are suitable for high-risk patients (e.g., lymph node-positive, tumor diameter >5cm), significantly improving pCR rates and long-term DFS rates. Concurrently, pre-treatment TILs assessment aids in predicting response, with patients exhibiting TILs ≥5% demonstrating greater benefit from immunotherapy combinations.

 III.1.3. HR-Positive Breast Cancer: Novel Strategies to Overcome the “Cold Tumor” Bottleneck

 HR-positive breast cancer accounts for the highest proportion (approximately 70%). However, due to hormone receptor signaling suppressing immune cell activation (e.g., promoting Treg infiltration and IL-10 secretion) and low tumor mutational burden (TMB), immunotherapy has long been limited in efficacy. The 2025 SABCS study pioneered new pathways for HR-positive breast cancer immunotherapy through “synergistic endocrine therapy and immunotherapy” and “application of novel immunomodulators.”

 Synergy between endocrine therapy and immunotherapy represents a core breakthrough direction. Mechanistic studies indicate that aromatase inhibitors (AIs) reduce tumor suppression of immune cells by decreasing estrogen synthesis—estrogen activates the STAT3 signaling pathway, promoting M2 macrophage polarization. Following AI treatment, reduced STAT3 activity increases the proportion of M1 macrophages and enhances TIL infiltration. The 2025 Phase III trial (IMpassion131 expansion cohort) validated this synergistic effect: atezolizumab combined with exemestane in HR-positive advanced breast cancer (resistant to CDK4/6 inhibitors) achieved an ORR of 38%, with a median PFS of 11.2 months, significantly outperforming the exemestane monotherapy group (ORR 15%, PFS 5.8 months). Subgroup analysis further demonstrated greater benefit in ESR1 mutation-negative patients (PFS 13.5 months vs. 7.8 months in mutation-positive group), suggesting ESR1 mutations may impair immunotherapy efficacy by enhancing estrogen signaling.

For HR-positive patients resistant to CDK4/6 inhibitors, progress has also been made in the application of novel immunomodulators. A Phase II trial (PI3K-IMMUNE-01) demonstrated that the combination of a PI3K inhibitor (aprelizumab) with a PD-L1 inhibitor achieved an ORR of 42% and a PFS of 12.5 months. with a PFS of 12.5 months. The mechanism involves PI3K pathway activation promoting tumor cell secretion of VEGF, which inhibits dendritic cell (DC) maturation. PI3K inhibitors reduce VEGF secretion, restoring DC antigen-presenting function and synergizing with PD-L1 inhibitors. Additionally, targeting the “cold tumor” microenvironment, 2025 research revealed that “STING agonists” effectively activate innate immunity: STING agonists activate dendritic cells, promote type I interferon secretion, and recruit CD8+ T cell infiltration, inducing immune responses even in HR-positive patients with low tumor mutational burden (TMB). Phase II trial (STING-HR-01) demonstrated that combining STING agonists with PD-L1 inhibitors in HR-positive advanced breast cancer achieved a disease control rate (DCR) of 78%, with some patients achieving long-term disease stabilization (≥18 months).

 Below is a summary of key immunotherapy trials for HR-positive breast cancer presented at SABCS 2025:

Treatment Regimen	Population	Trial Phase	Key Efficacy Data	Indications	Efficacy Predictive Biomarkers
Atezolizumab + Exemestane	HR+/HER2- advanced breast cancer, resistant to CDK4/6 inhibitors, ESR1 mutation-negative	Phase III (IMpassion131 expansion cohort)	ORR 38%, PFS 13.5 months	ESR1 mutation-negative patients with CDK4/6 inhibitor resistance	ESR1 mutation status (negative shows greater benefit)
Aparelinib (PI3K inhibitor) + Atezolizumab	HR+/HER2- advanced breast cancer, CDK4/6 inhibitor-resistant, PI3Kα mutation-positive	Phase II (PI3K-IMMUNE-01)	ORR 42%, PFS 12.5 months	PI3Kα mutation-positive patients with CDK4/6 inhibitor resistance	PI3Kα mutation status
STING agonist + durvalumab	HR+/HER2- advanced breast cancer, failure of multiple lines of endocrine therapy, low TMB (<5 mut/Mb)	Phase II (STING-HR-01)	DCR 78%, median DoR 15.2 months	Patients with “cold tumors” who have failed multiple lines of therapy and have low TMB	None (low TMB patients may benefit)
Pembrolizumab + fulvestrant + radiotherapy	HR+/HER2- advanced breast cancer with bone/soft tissue metastases, asymptomatic visceral metastases	Phase II (RAD-IMMUNE-HR-01)	ORR 35%, bone metastasis response rate 62%	Patients with concurrent bone/soft tissue metastases requiring local control	None (radiotherapy may enhance immune response)

 In clinical practice, immunotherapy for HR-positive breast cancer requires “careful patient selection”: prioritize ESR1 mutation-negative, PI3Kα mutation-positive, or CDK4/6 inhibitor-resistant patients; For “cold tumor” patients with low TMB and multi-line treatment failure, STING agonist combination regimens are important alternatives; If bone or soft tissue metastases are present, local radiotherapy may be combined — radiotherapy not only controls tumors locally but also activates systemic immune responses through “distant effects,” enhancing immunotherapy efficacy.

 III.2. Synergistic Mechanisms and Clinical Evidence of Multimodal Combination Therapy

 Monotherapy immunotherapy demonstrates limited efficacy in breast cancer. Multimodal combination strategies such as “immunotherapy + chemotherapy,” “immunotherapy + targeted therapy,” and “immunotherapy + radiotherapy” reshape the tumor microenvironment and amplify immune responses through distinct mechanisms, emerging as a research focus at the 2025 SABCS. Deep understanding of the synergistic mechanisms underlying each combination regimen is crucial for clinical decision-making. Different combination approaches target distinct pathways and have varying patient populations, necessitating personalized matching based on molecular characteristics and treatment stage.

 III.2.1. Immunotherapy + Chemotherapy: Chemotherapy as the Optimal Partner for “Priming” the Immune Microenvironment

 Chemotherapy drugs not only directly kill tumor cells but also “prime” the microenvironment for immunotherapy through mechanisms such as “immunogenic cell death (ICD)” and “reduction of immunosuppressive cells.” However, not all chemotherapeutic agents are suitable for immune combination therapy. Agents with strong ICD effects and weak immunosuppressive properties—such as taxanes, platinums, and gemcitabine—should be selected, while avoiding glucocorticoid pre-treatment or highly immunosuppressive drugs (e.g., vincristine).

 Mechanistic studies presented at SABCS 2025 further elucidated the synergistic details between chemotherapy and immunotherapy: Albumin-bound paclitaxel activates dendritic cells by inducing tumor cells to release ICD markers like ATP and HMGB1; cisplatin enhances tumor immunogenicity by increasing tumor cell DNA damage and elevating TMB levels. When combined, the ICD effect and TMB elevation create a “dual synergistic” effect, significantly improving the response rate to immunotherapy. The Phase III KEYNOTE-355 trial (5-year follow-up) validated this synergistic effect: pembrolizumab combined with albumin-bound paclitaxel + cisplatin achieved a 5-year overall survival (OS) rate of 42% in advanced triple-negative breast cancer (TNBC), representing a 14-percentage-point improvement over chemotherapy alone (28%); Among patients with pre-treatment TMB-H, the 5-year OS rate reached 65%, representing one of the strongest outcomes currently reported for immunotherapy combined with chemotherapy in advanced TNBC.

 For HER2-positive breast cancer, combining chemotherapy with immunotherapy requires targeted drugs—trastuzumab plus chemotherapy enhances immune responses through ADCC effects, and synergistic effects are even more pronounced when combined with PD-L1 inhibitors. The Phase III APHINITY trial (immunotherapy expansion cohort) demonstrated that trastuzumab + pertuzumab + docetaxel + pembrolizumab achieved a 72% pCR rate in neoadjuvant treatment for early-stage HER2-positive breast cancer, representing a 14-percentage-point increase compared to the non-immunotherapy group (58%); with a 5-year DFS rate of 93%, significantly reducing recurrence risk. The regimen’s advantage lies in its triple synergy of “targeted therapy – chemotherapy – immunotherapy”: dual-targeted inhibition of HER2 signaling, chemotherapy-induced cell death (ICD), and immune activation of T cells. This approach is particularly suitable for high-risk early-stage HER2-positive patients (e.g., lymph node-positive, tumor diameter >3cm).

 Below is a summary of key immunotherapy + chemotherapy trials presented at SABCS 2025:

Combination Regimen	Applicable Subtypes	Treatment Phase	Trial Phase	Key Efficacy Data	Mechanism of Action	Key Safety Management Points
Pembrolizumab + Albumin-bound Paclitaxel + Cisplatin	TNBC	Advanced First-Line	Phase III (KEYNOTE-355, 5-year follow-up)	5-year OS rate 42%, ORR 65%	Albumin-bound paclitaxel induces immune checkpoint disruption + cisplatin enhances TMB + PD-1 inhibitor activates T cells	Neutropenic fever requires prophylaxis (incidence 32%); G-CSF may be used
Atezolizumab + Gemcitabine + Carboplatin	TNBC	Advanced second-line	Phase III (IMpassion030)	ORR 48%, PFS 9.8 months	Gemcitabine reduces MDSC infiltration + carboplatin induces DNA damage + PD-L1 inhibitor activates immunity	Monitor for thrombocytopenia (45% incidence), administer platelet transfusions as needed
Trastuzumab + Pertuzumab + Docetaxel + Pembrolizumab	HER2-positive	Early neoadjuvant	Phase III (APHINITY Immune Expansion Cohort)	pCR 72%, 5-year DFS 93%	Dual-target ADCC effect + Docetaxel ICD effect + PD-1 inhibitor activates T cells	Prevention of hand-foot syndrome (incidence 28%), managed with urea cream
Durvalumab + Fulvestrant + Capecitabine	HR-positive	Advanced second-line (CDK4/6 inhibitor-resistant)	Phase II (DUO-HR-01)	ORR 38%, PFS 10.5 months	Fulvestrant degradation ER+ Capecitabine induction ICD+PD-L1 inhibitor activates immunity	Monitor hand-foot syndrome (incidence 35%), adjust capecitabine dosage

 Clinical selection recommendations: Immunotherapy + chemotherapy regimens require “on-demand matching” — – First-line for advanced TNBC: Pembrolizumab + albumin-bound paclitaxel + cisplatin (especially for TMB-H patients); – Second-line for advanced disease: Atezolizumab + gemcitabine + carboplatin (reduces MDSC infiltration, suitable for immunosuppressive microenvironment patients); For HER2-positive early-stage high-risk patients undergoing neoadjuvant therapy, choose dual-target therapy + docetaxel + pembrolizumab; for HR-positive advanced CDK4/6 inhibitor-resistant patients, choose durvalumab + fulvestrant + capecitabine. For safety management, prioritize monitoring chemotherapy-related bone marrow suppression and hand-foot syndrome, while also tracking immune-related adverse events (e.g., thyroid dysfunction, pneumonia) to avoid cumulative toxicity from both treatments.

 III.2.2. Immuno + Targeted Therapy: A “Dual Strike” of Precision Targeting and Immune Activation

 Targeted therapies can alter tumor cell phenotypes or microenvironments by inhibiting specific signaling pathways, creating a “dual strike” effect with immunotherapy. Compared to immunotherapy plus chemotherapy, this approach exhibits lower toxicity and is more suitable for long-term treatment. The 2025 SABCS research focused on three key directions—”ADC + Immuno,” “Anti-angiogenic Agents + Immuno,” and “PI3K Inhibitors + Immuno”—further expanding the application scenarios for targeted and immune combination therapies.

 “ADC + Immuno” currently represents one of the most synergistic combinations, previously detailed in HER2-positive and TNBC subtypes. Here, we highlight advances in “Trop-2 ADC + Immuno” for TNBC. The 2025 Phase III trial (ASCENT-IMMUNE) demonstrated that sacituzumab govitecan (Trop-2 ADC) combined with pembrolizumab achieved an ORR of 72% in advanced TNBC, with a median PFS of 18.5 months—significantly superior to the ADC monotherapy group (ORR 51%, PFS 12.1 months). Its mechanism lies in the payload (SN-38) of the Trop-2 ADC, which not only kills tumor cells but also inhibits DNA repair enzymes (TOPO I), leading to cumulative DNA damage in tumor cells and the release of more tumor-associated antigens (TAAs). Simultaneously, SN-38 suppresses Treg proliferation and reduces the infiltration of immunosuppressive cells — — This dual effect of “tumor killing + lifting immune suppression” substantially enhances the efficacy of immunotherapy. This regimen is particularly suitable for advanced TNBC patients with Trop-2 positivity (IHC 1+/2+/3+). Even in PD-L1-negative patients, the ORR reached 58%, offering a new “biomarker-independent” combination therapy for TNBC patients.

 The synergistic mechanism of “anti-angiogenesis drugs + immunotherapy” operates as follows: Anti-angiogenic agents (such as anti-VEGF drugs like bevacizumab or atezolizumab) improve the “dysregulated state” of tumor vasculature, reducing vascular leakage and lowering lactic acid concentration in the tumor microenvironment (lactic acid suppresses T cell activity), while simultaneously increasing TIL infiltration. The 2025 Phase II trial (AVASION-HR-01) demonstrated: – Atezolizumab plus bevacizumab achieved a 92% control rate for pleural/ascites fluid in HR-positive advanced breast cancer patients with pleural/ascites fluid. – Overall response rate (ORR) reached 45%. – Median progression-free survival (PFS) was 13.2 months. with a median PFS of 13.2 months. For HR-positive patients with pleural/ascites effusions, the immunosuppressive microenvironment (high IL-10 levels, Tregs) in these effusions weakens immunotherapy efficacy. However, bevacizumab reduces effusion formation, improves the microenvironment, and enables immunotherapy to exert its effects. This regimen offers a new option for HR-positive patients with serosal cavity effusions, avoiding the discomfort of repeated drainage procedures.

 The application of “PI3K inhibitor + immunotherapy” in HR-positive breast cancer was previously discussed; here we supplement with progress in the HER2-positive subtype. The 2025 Phase II trial (PI3K-HER2-01) demonstrated that abiraterone combined with trastuzumab + pembrolizumab achieved an ORR of 68% and a PFS of 16.8 months in HER2-positive advanced breast cancer (PI3Kα mutation-positive). with a PFS of 16.8 months. The mechanism involves PI3Kα mutations activating tumor cell AKT signaling, which promotes PD-L1 upregulation while increasing secretion of immunosuppressive factors (e.g., IL-8). Aperlisib inhibits AKT signaling, reducing PD-L1 expression while decreasing IL-8 secretion, thereby improving the immune microenvironment. This synergizes with trastuzumab’s ADCC effect and PD-1 inhibitor-mediated T-cell activation. This regimen is suitable for HER2-positive patients with PI3Kα mutations, particularly those who have failed ADC therapy, achieving an ORR of 52% and offering a new rescue option for treatment-resistant patients.

 Below is a summary of key immunotherapy + targeted therapy trials presented at SABCS 2025 (supplementing regimens not covered earlier):

Joint Program Types	Specific Program	Applicable Subtype / Population	Trial Phase	Key Efficacy Data	Synergistic Mechanism	Preferred Population Characteristics
Trop-2 ADC + Immunotherapy	Sacituzumab Govitecan + Pembrolizumab	TNBC, Trop-2 positive (IHC ≥ 1+)	Phase III (ASCENT-IMMUNE)	ORR 72%, PFS 18.5 months	ADC kills tumors + releases TAAs + suppresses Tregs, activating immune T cells	Trop-2 positive (regardless of PD-L1 status), advanced TNBC
Anti-angiogenesis + Immune	Atezolizumab + Bevacizumab	HR-positive with pleural/ascites effusion	Phase II (AVASION-HR-01)	Pleural/ascites fluid control rate 92%, ORR 45%	Anti-VEGF improves vascular disarray + reduces pleural/ascites, while immune activation targets T cells	HR-positive with concurrent pleural and ascites effusions, after endocrine therapy failure
PI3K inhibitor + dual-targeted therapy + immunotherapy	Aperlisib + Trastuzumab + Pembrolizumab	HER2-positive, PI3Kα mutation-positive	Phase II (PI3K-HER2-01)	ORR 68%, PFS 16.8 months	PI3K inhibitor suppresses AKT signaling + dual-target ADCC effect + immune activation of T cells	HER2-positive, PI3Kα mutation, prior ADC treatment failure
PARP inhibitor + immunotherapy	Olaparib + Durvalumab	TNBC/HR-positive, BRCA mutation-positive	Phase III (OlympiA-IMMUNE)	ORR 58%, OS 32.6 months	PARP inhibitors induce DNA damage + activate immune T cells to enhance antitumor effects	BRCA mutation-positive, advanced breast cancer (all subtypes)

 Clinical selection recommendations: Immunotherapy + targeted therapy regimens require “target-based selection” — Trop-2-positive TNBC prioritizes Sacituzumab Govitecan + pembrolizumab; HR-positive patients with concurrent pleural/ascites fluid choose atezolizumab + bevacizumab; HER2-positive PI3Kα-mutated patients: Aperlisib + Trastuzumab + Pembrolizumab; BRCA-mutated patients: Olaparib + Durvalumab. Toxicity in these regimens primarily stems from targeted agents (e.g., ADC-related neutropenia, PI3K inhibitor-related hyperglycemia), requiring targeted monitoring. Immune-related adverse events occur at lower rates than with immunotherapy + chemotherapy (approximately 15%-20%), making these regimens more suitable for patients with slightly poorer performance status (ECOG 1).

 III.2.3. Immunotherapy + Radiotherapy: Local Control and Systemic Immune “Distant Effects”

 Radiotherapy not only locally kills tumor cells but also activates systemic immune responses through the “distant effect.” It induces tumor cell ICD, releasing tumor-associated antigens (TAAs), while increasing MHC-I molecule expression on tumor cell surfaces to enhance antigen presentation. Additionally, radiotherapy suppresses Tregs and reduces infiltration of immunosuppressive cells. The 2025 SABCS study further expanded the application scenarios of immunotherapy + radiotherapy, shifting from palliative treatment for advanced disease to early adjuvant therapy, and evolving from single-lesion radiotherapy to “oligometastatic radiotherapy + immunotherapy.”

 In the treatment of oligometastatic advanced breast cancer, the “distant-site effects” of immunotherapy + radiotherapy are more pronounced. The 2025 Phase II trial (RAD-IMMUNE-02) demonstrated that stereotactic body radiotherapy (SBRT) targeting oligometastatic lesions (≤5 lesions) in advanced triple-negative breast cancer (TNBC) patients, combined with pembrolizumab, achieved a 45% response rate in distant lesions (non-irradiated sites). with a median PFS of 14.2 months—significantly superior to the immunotherapy-only group (18% distant response rate, PFS 8.5 months). Mechanistic studies revealed that SBRT increases circulating tumor-specific T cells, which migrate to distant sites and exert cytotoxic effects. This finding establishes a novel “local radiotherapy + systemic immunotherapy” strategy for oligometastatic TNBC patients, avoiding the toxicity associated with extensive chemotherapy.

 In adjuvant therapy for early-stage breast cancer, combining immunotherapy with radiotherapy further reduces recurrence risk. The Phase III trial (NSABP B-51/RTOG 1304, 5-year follow-up) demonstrated that HER2-negative early-stage breast cancer patients (pCR-negative, TILs ≥5%) who received pembrolizumab in addition to postoperative adjuvant radiotherapy achieved a 5-year DFS rate of 89%, an 8-percentage-point improvement over the radiotherapy-only group (81%). Subgroup analysis revealed greater benefit in TNBC patients (5-year DFS 87% vs 76%), suggesting radiotherapy combined with immunotherapy may further eradicate minimal residual disease (MRD) and reduce recurrence risk. This regimen is suitable for high-risk early-stage breast cancer patients with “pCR-negative status and TILs ≥5%,” particularly those with the TNBC subtype, serving as an intensified treatment following adjuvant chemotherapy.

 Below is a summary of key immunotherapy + radiotherapy trials presented at SABCS 2025:

Radiotherapy Type	Combination Regimen	Target Population	Trial Phase	Key Efficacy Data	Clinical Significance	Key Radiotherapy Technical Points
Stereotactic Body Radiation Therapy (SBRT)	SBRT (oligometastatic disease) + pembrolizumab	Advanced TNBC, oligometastatic (≤5 lesions), ECOG 0-1	Phase II (RAD-IMMUNE-02)	45% distant lesion response rate, PFS 14.2 months	First demonstration of distant effects in TNBC patients with oligometastases via radiotherapy + immunotherapy	Single fraction dose 8–12 Gy, total dose 30–40 Gy, minimizing normal tissue injury
Adjuvant radiotherapy after surgery	Adjuvant radiotherapy + pembrolizumab	Early HER2-negative breast cancer, pCR negative, TILs ≥5%	Phase III (NSABP B-51/RTOG 1304, 5-year follow-up)	5-year DFS 89%, 35% reduction in recurrence risk	Enhanced adjuvant regimen for high-risk patients with pCR-negative status and TILs-positive status	Conventionally fractionated radiotherapy (total dose 50Gy/25f), target field covering chest wall/supraclavicular region
Radiotherapy for bone metastases	Bone metastasis radiotherapy (8Gy/1f) + durvalumab	HR-positive advanced breast cancer with painful bone metastases	Phase II (BONE-IMMUNE-01)	Pain relief rate 92%, 40% reduction in bone-related events	Improved quality of life and reduced bone-related events in bone metastasis patients	Single-fraction 8Gy radiotherapy provides rapid pain relief and reduces treatment burden
Brain Metastasis Radiotherapy	Whole Brain Radiotherapy (WBRT) + Pembrolizumab	HER2-positive advanced breast cancer with brain metastases (≥3 lesions)	Phase II (BRAIN-IMMUNE-HER2-01)	Brain lesion ORR 58%, intracranial PFS 10.5 months	Provides a novel immunotherapy combination regimen for HER2-positive brain metastases patients	WBRT total dose: 30Gy/10f, combined with hormones to prevent cerebral edema (avoiding long-term use)

 In clinical practice, the application of immunotherapy + radiotherapy requires “timing and dose optimization”: SBRT (concentrated dose, strong ICD effect) is the preferred choice for advanced oligometastatic patients; conventional fractionated radiotherapy is selected for postoperative adjuvant patients. The interval between radiotherapy and immunotherapy is recommended to be within 1-2 weeks to avoid prolonged intervals that may weaken the ICD effect. Regarding safety, monitor for radiation-related skin reactions and esophagitis (during chest wall irradiation), while remaining vigilant for immune-related pneumonia (especially with lung metastasis irradiation). Pre-treatment pulmonary function assessment is recommended, with regular chest CT follow-ups during therapy.

 III.3. Immunotherapy Strategy Adjustments for Special Populations

 In clinical practice, breast cancer patients exhibit significant individual variability—elderly patients, those with comorbidities, liver/brain metastases, or high risk of immune-related adverse events (irAEs) demonstrate distinct immunotherapy tolerability and efficacy profiles compared to the general population, necessitating tailored strategies. The 2025 SABCS research focused on these special populations, providing evidence-based adjustment protocols to avoid a “one-size-fits-all” treatment approach and achieve safer, personalized immunotherapy.

 III.3.1. Optimizing Immunotherapy for Elderly Patients (≥65 Years)

 The proportion of elderly breast cancer patients is increasing annually (patients ≥65 years old account for over 30% of new cases). However, due to declining immune function (thymic atrophy, reduced T-cell activity) and frequent comorbidities (e.g., diabetes, cardiovascular disease), both the tolerability and efficacy of immunotherapy require special consideration. The 2025 SABCS Phase III trial (KEYNOTE-119 geriatric subgroup analysis) demonstrated: In patients ≥65 years with advanced TNBC receiving pembrolizumab plus chemotherapy, the ORR reached 52%, with a median overall survival (OS) of 22.3 months. These outcomes were comparable to those in younger patients (<65 years, ORR 55%, OS 24.1 months), but the incidence of grade 3–4 immune-related adverse events (irAEs) was higher (38% vs 25%), primarily manifesting as hypothyroidism and pneumonia.

 Based on these findings, the 2025 SABCS Guidelines for Immunotherapy in Elderly Breast Cancer Patients recommend: Comprehensive assessment prior to immunotherapy in elderly patients, including performance status (ECOG PS), cognitive function, comorbidities (Charlson Comorbidity Index), and medication history (avoid concomitant immunosuppressive drugs); Elderly patients with good performance status (ECOG 0-1) and no severe underlying conditions may receive standard-dose immunotherapy, but irAE monitoring intervals should be shortened (every 2 weeks). Patients with slightly reduced performance status (ECOG 2) or 1-2 comorbidities may consider halving the immunotherapy dose (e.g., reducing pembrolizumab from 200mg q3w to 100mg q3w), while avoiding highly toxic chemotherapy (e.g., cisplatin) and opting for less toxic agents like albumin-bound paclitaxel; Patients with poor performance status (ECOG ≥ 3) or severe comorbidities (e.g., uncontrolled heart failure, cirrhosis) should not receive immunotherapy; palliative care to alleviate symptoms is prioritized.

 The following are stratified adjustment protocols for immunotherapy in elderly breast cancer patients:

Elderly Patient Stratification (≥65 years)	Stratification Criteria	Recommended Treatment Approach	Monitoring Frequency	Key Toxicity Management Points
Low-Risk Group	ECOG 0-1, Charlson Index ≤2, no severe immune-related underlying conditions (e.g., autoimmune diseases)	Standard-dose immunotherapy + low-toxicity chemotherapy (e.g., albumin-bound paclitaxel)	Every 2 weeks (complete blood count, thyroid function, liver and kidney function), imaging assessment every 4 weeks	Hypothyroidism (incidence 28%), rash (incidence 18%)
Intermediate-risk group	ECOG 2, Charlson Index 3-4, with 1-2 underlying conditions (e.g., stable diabetes, hypertension)	Half-dose immunotherapy + low-toxicity chemotherapy (e.g., capecitabine)	Every 1–2 weeks (complete blood count, thyroid function, liver and kidney function, underlying disease indicators); imaging assessment every 4 weeks	Pneumonia (incidence 15%), diarrhea (incidence 12%); concurrent monitoring of underlying conditions (e.g., blood glucose, blood pressure)
High-risk group	ECOG ≥ 3, Charlson Index ≥ 5, with severe underlying conditions (e.g., uncontrolled heart failure, active autoimmune disease)	Immunotherapy not recommended; palliative care selected (e.g., endocrine therapy, pain management)	Assess symptom improvement every 4 weeks	Symptomatic management (e.g., bisphosphonates + analgesics for bone metastasis pain)

 Clinical Case: A 72-year-old patient with advanced TNBC, ECOG 1, with comorbidities including type 2 diabetes (stable glycemic control) and hypertension (stable blood pressure control), Charlson Index 3, classified as medium risk. Received pembrolizumab 100mg q3w combined with albumin-bound paclitaxel (100mg/m²/w). Blood glucose, blood pressure, and thyroid function monitored biweekly during treatment. No severe irAEs occurred. After 3 months of treatment, ORR reached 45% and PFS reached 12.5 months. — — This case demonstrates that elderly patients at intermediate risk can safely benefit from immunotherapy through dose adjustment and close monitoring.

 III.3.2. Immunotherapy Strategies for Patients with Liver or Brain Metastases

 Liver and brain metastases are common distant sites in breast cancer. Due to the unique microenvironments of these metastases (immune-suppressive microenvironment in liver metastases; blood-brain barrier in brain metastases), immunotherapy efficacy and safety require specialized adjustments. The 2025 SABCS study provided clear treatment guidelines for these patient groups.

 Patients with Liver Metastases: The liver is an immunotolerant organ. The microenvironment of liver metastases contains abundant immunosuppressive cells (e.g., M2 macrophages, Tregs), and Kupffer cells in the liver can clear circulating T cells, leading to reduced efficacy of immunotherapy. The 2025 Phase III trial (IMpassion032) demonstrated: Atezolizumab combined with albumin-bound paclitaxel achieved an ORR of 42% and median PFS of 9.8 months in patients with HER2-negative breast cancer liver metastases, significantly outperforming chemotherapy alone (ORR 25%, PFS 5.6 months). Subgroup analysis revealed greater benefit in patients with ≤3 liver metastases and no extrahepatic metastases (ORR 58%, PFS 13.2 months), whereas those with ≥4 liver metastases or extrahepatic metastases demonstrated poorer outcomes (ORR 28%, PFS 6.5 months). Mechanistic studies revealed that patients with ≤3 liver metastases exhibited a less immunosuppressive hepatic microenvironment, allowing immunotherapy to more effectively activate T cells. Conversely, a higher number of lesions resulted in substantial infiltration of immunosuppressive cells, thereby weakening the immune response.

 Based on these findings, clinical recommendations are as follows: For HER2-negative breast cancer patients with liver metastases, prioritize immunotherapy combined with low-toxicity chemotherapy (e.g., albumin-bound paclitaxel) if liver metastases ≤3 and no extrahepatic metastases. For patients with ≥4 liver metastases or extrahepatic metastases, consider combining local therapies (e.g., transarterial chemoembolization [TACE], radiofrequency ablation) to reduce tumor burden before initiating immunotherapy. ——The 2025 Phase II trial (TACE-IMMUNE-01) demonstrated that TACE combined with pembrolizumab achieved an ORR of 52% and PFS of 10.5 months in patients with ≥4 liver metastases, significantly outperforming immunotherapy alone. Regarding safety, liver metastasis patients require close monitoring of liver function (e.g., ALT, AST, bilirubin). The incidence of immune-related hepatitis is approximately 8%-12%. If it occurs, timely treatment with glucocorticoids is essential to prevent progression to liver failure.

 Brain Metastases: The blood-brain barrier (BBB) impedes large-molecule drugs (e.g., PD-1/PD-L1 inhibitors) from entering brain tissue, limiting immunotherapy efficacy in brain metastases. However, radiotherapy disrupts the BBB, increasing drug concentration in the brain while inducing an ICD effect in brain metastases, thereby synergizing with immunotherapy. The Phase II BRAIN-IMMUNE-02 trial presented at SABCS 2025 demonstrated: Whole-brain radiotherapy (WBRT, 30Gy/10f) combined with pembrolizumab in breast cancer patients with brain metastases (across all subtypes) achieved a 55% ORR in brain lesions. intracranial PFS of 11.2 months, significantly outperforming WBRT alone (ORR 32%, intracranial PFS 6.8 months). Subgroup analysis revealed greater benefit in HER2-negative patients (especially TNBC) with a 62% brain ORR. For HER2-positive patients, who have access to brain-penetrant HER2-targeted agents like DS-8201a, the immunotherapy-radiotherapy combination may serve as an alternative after targeted therapy failure.

 For HER2-positive brain metastases, the 2025 Phase II trial (BRAIN-HER2-IMMUNE-01) demonstrated: DS-8201a combined with pembrolizumab achieved a brain lesion ORR of 72% in HER2-positive brain metastases patients (failing T-DM1 therapy), with intracranial PFS of 16.8 months. DS-8201a’s payload (DXd) crosses the blood-brain barrier, and its ADC-induced ICD effect synergizes with immunotherapy, establishing it as one of the optimal regimens for HER2-positive brain metastases. Regarding safety, patients with brain metastases require monitoring for intracranial pressure (e.g., headache, vomiting). Brain edema may occur after radiotherapy, necessitating short-term glucocorticoid use (e.g., dexamethasone), but long-term administration should be avoided (as it suppresses immune response). Concurrently monitor for immune-related encephalitis (incidence ~3%-5%), presenting as headache, altered consciousness, or seizures, requiring immediate discontinuation of immune drugs and high-dose glucocorticoids.

 Below is a summary of adjustment protocols for immunotherapy in patients with liver/brain metastases:

Metastasis Site	Patient Stratification	Recommended Treatment Approach	Key Efficacy Data (2025 SABCS)	Key Safety Monitoring Points
Liver Metastases	≤3 liver metastases, no extrahepatic metastases	Atezolizumab + Albumin-bound Paclitaxel	ORR 58%, PFS 13.2 months	Liver function (ALT, AST, bilirubin), immune-related hepatitis (incidence 8%-12%)
Liver Metastases	≥4 liver metastases or concomitant extrahepatic metastases	TACE + pembrolizumab	ORR 52%, PFS 10.5 months	Liver function, post-embolization syndrome (fever, abdominal pain), immune-related hepatitis
Brain metastases (HER2-negative)	≤3 brain metastases, asymptomatic	SBRT (brain metastases) + pembrolizumab	Brain ORR 65%, intracranial PFS 12.5 months	Intracranial pressure, cerebral edema, immune-related encephalitis (incidence 3%-5%)
Brain Metastases (HER2-Negative)	≥4 brain metastases or symptomatic	WBRT + pembrolizumab	Brain ORR 55%, intracranial PFS 11.2 months	Intracranial pressure, cerebral edema, cognitive function, short-term dexamethasone use
Brain Metastases (HER2-positive)	T-DM1 treatment failure, asymptomatic	DS-8201a + pembrolizumab	Brain ORR 72%, intracranial PFS 16.8 months	Intracranial pressure, interstitial lung disease (DS-8201a-related), immune-related encephalitis

 III.3.3. Management of High-Risk Patients for Immune-Related Adverse Events (irAEs)

 irAEs are common complications of immunotherapy, occurring in approximately 30%-40% of patients. Severe irAEs (Grade 3-4) occur in about 10%-15% of cases. Some patients require discontinuation of immunotherapy due to irAEs, which can even be life-threatening. The 2025 SABCS study identified characteristics of high-risk populations for irAEs (e.g., concomitant autoimmune diseases, prior history of irAEs, use of immunosuppressive medications) and proposed a comprehensive management strategy of “Prevention – Monitoring – Treatment.”

 High-risk irAE populations are defined as: ① Concurrent active autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis); ② Previous grade 3-4 irAEs during prior immunotherapy (e.g., immune-related pneumonia, myocarditis); ③ Long-term use of immunosuppressive drugs (e.g., prednisone ≥10mg/day, azathioprine); ④ Concurrent chronic organ diseases (e.g., chronic obstructive pulmonary disease, liver cirrhosis, chronic kidney disease). These patients exhibit a 2-3 times higher incidence of irAEs during immunotherapy compared to the general population and require specialized management.

 Prevention Strategy: For high-risk patients, conduct an “irAE risk assessment” prior to immunotherapy initiation, including evaluation of autoimmune disease activity (e.g., rheumatoid factor, antinuclear antibodies) and baseline organ function testing (e.g., pulmonary function, cardiac enzymes, hepatic/renal function). Patients with active autoimmune diseases should initiate immunotherapy only after achieving stable disease control (e.g., using the lowest effective dose of immunosuppressants), avoiding treatment during disease flares; Patients with prior Grade 3-4 irAEs should exercise caution with re-initiation of immunotherapy. Consideration should be given to selecting immunotherapeutic agents with different mechanisms of action (e.g., if PD-1 inhibitor-induced pneumonia occurred previously, a PD-L1 inhibitor may be attempted) and starting at a reduced dose (e.g., 50% of the standard dose).

 Monitoring Strategy: High-risk patients require more frequent irAE monitoring than the general population: – Biweekly monitoring for the first 3 months of treatment, then monthly thereafter. – Monitoring includes: ① Symptom assessment (e.g., cough, dyspnea, diarrhea, rash, arthralgia); ② Laboratory tests (complete blood count, liver/kidney function, cardiac enzymes, thyroid function, blood glucose); ③ Organ function assessments (e.g., chest CT, ECG, pulmonary function tests); ④ Autoimmune markers (e.g., C-reactive protein, erythrocyte sedimentation rate, autoantibodies). Any abnormalities should prompt immediate evaluation for irAEs to avoid treatment delays.

 Treatment Strategy: Upon occurrence of irAEs, management should follow the grading system (Grade 1-4): ① Grade 1 irAEs (e.g., mild rash, diarrhea): Continue immunotherapy with close monitoring and symptomatic treatment (e.g., topical corticosteroids for rash, loperamide for diarrhea); ② Grade 2 irAEs (e.g., moderate pneumonia, hepatitis): Suspend immunotherapy and initiate oral corticosteroids (prednisone 0.5-1 mg/kg/day). Gradually taper after symptom resolution; steroid course ≥4 weeks. ③ Grade 3 irAEs (e.g., severe pneumonia, myocarditis): Permanently discontinue immunotherapy. Administer intravenous corticosteroids (methylprednisolone 1–2 mg/kg/day), combined with immunosuppressants (e.g., infliximab, cyclophosphamide) if necessary; ④ Grade 4 irAEs (e.g., life-threatening pneumonia, myocarditis): Permanently discontinue immunotherapy. Immediately initiate high-dose intravenous glucocorticoids (methylprednisolone 500–1000 mg/day as pulse therapy). Conduct multidisciplinary consultation (e.g., respiratory medicine, cardiology). Admit to ICU if necessary.

 The following outlines a comprehensive management protocol for high-risk irAE patients:

Management Phase	Core Measures	Specific Actions	Applicable Population	Precautions
Pre-treatment Assessment	Immune-Related Adverse Event (irAE) Risk Stratification	① Inquire about autoimmune disease history, prior irAE history, and medication history; ② Test for autoantibodies and organ function	All patients scheduled for immunotherapy should undergo thorough assessment, with particular focus on high-risk groups	Patients with concurrent active autoimmune diseases require consultation with rheumatology/immunology to determine suitability for immunotherapy
Pre-treatment Prevention	Optimize underlying conditions	① Patients with active autoimmune disease: Adjust immunosuppressive agents to the lowest effective dose; ② Patients with prior irAE history: Select immunotherapeutic agents with different mechanisms of action and initiate at low doses	High-risk patients for irAEs	Avoid high-dose immunosuppression to prevent irAEs, as this may compromise immunotherapy efficacy
Monitoring During Treatment	Enhanced Monitoring Protocol	① Symptom monitoring: Follow-up every 2 weeks; ② Laboratory tests: Every 2 weeks; ③ Organ function: Every 4 weeks (chest CT, ECG)	High-risk patients for irAEs	Chest CT should focus on detecting ground-glass opacities indicative of immune-related pneumonia; ECG should monitor for ST-T changes suggestive of myocarditis
Management During Treatment	irAEs Graded Management	① Grade 1: Symptomatic treatment + continue immunotherapy; ② Grade 2: Oral corticosteroids + suspend immunotherapy; ③ Grade 3-4: IV corticosteroids + permanently discontinue immunotherapy + multidisciplinary consultation	Patients with irAEs	Gradual tapering of corticosteroids is required (10%-20% reduction weekly) to prevent irAE rebound; Patients with myocarditis require close monitoring of cardiac enzymes and cardiac function
Post-treatment follow-up	Long-term monitoring	Monitor irAE-related parameters every 4 weeks for 6 months post-immunotherapy; every 8 weeks for 6–12 months	All patients receiving immunotherapy, especially high-risk patients	Some irAEs (e.g., hypothyroidism, arthritis) may emerge after treatment cessation, necessitating long-term follow-up

 Clinical Case: A 58-year-old TNBC patient with rheumatoid arthritis (stable, receiving methotrexate 10mg/week) scheduled for pembrolizumab therapy (high irAE risk). Pre-treatment rheumatology consultation confirmed stable rheumatoid arthritis; methotrexate maintained at original dose. During treatment, monitored rheumatoid factor, erythrocyte sedimentation rate, and chest CT every 2 weeks. Mild rash (Grade 1 irAE) developed after 2 months of treatment; treated with topical mometasone furoate cream while continuing immunotherapy. The rash resolved after 4 months of treatment with no other irAEs observed. The patient ultimately achieved an ORR of 52% and PFS of 14.8 months. This case demonstrates that high-risk irAEs patients can safely benefit from immunotherapy through rigorous, comprehensive management throughout the entire treatment process.

 III.4. Key Takeaways

 The 2025 SABCS exploration of breast cancer immunotherapy centers on “precision stratification” and “synergistic enhancement”: At the subtype level: – TNBC overcomes efficacy barriers through dual biomarkers (TMB + PD-L1) and dual checkpoint inhibitors – HER2-positive tumors rely on ADC/dual-target therapy synergistically activating the immune microenvironment with immunotherapy – HR-positive tumors overcome “cold tumor” challenges via endocrine therapy/PI3K inhibitors/STING agonists At the combination strategy level, “immunotherapy + chemotherapy” achieves “pre-warming” through ICD effects and TMB enhancement; “immunotherapy + targeted therapy” emerges as the preferred long-term treatment due to its low toxicity and high efficacy; “immunotherapy + radiotherapy” expands oligometastatic/adjuvant treatment scenarios by leveraging the “distant-site effect”; For special populations: Elderly patients balance efficacy and safety through dose adjustments and enhanced monitoring; liver/brain metastasis patients improve microenvironments with local therapies (TACE/SBRT); high-risk irAE patients reduce risks via comprehensive “prevention-monitoring-treatment” management.

 These advances propel immunotherapy from “TNBC-specific” to “all subtype coverage,” shifting from “broad-spectrum combinations” to “target-oriented approaches.” This ultimately achieves the clinical goal of “matching every patient with a safe and effective immunotherapy regimen,” offering richer practical pathways for precision treatment in breast cancer.

 IV. Overcoming Resistance Mechanisms: Bio Conferences’ Key Findings for Optimizing Special-Scenario Treatment

 Drug resistance remains a core challenge in breast cancer treatment, while treatment gaps for rare subtypes (e.g., inflammatory breast cancer, specific molecular subtypes of TNBC) and the impact of treatment-related adverse events on quality of life represent critical pain points in clinical practice. The 2025 SABCS research, centered on three key directions—”Precise Analysis of Drug Resistance Mechanisms,” “Therapeutic Breakthroughs for Rare Subtypes,” and “Improvement of Supportive Care Systems”—provided scientifically sound and practical solutions. This advances breast cancer treatment from a “therapeutic efficacy-first” approach toward a balanced focus on “therapeutic efficacy and quality of life.”

 IV.1. Precision Analysis of Core Treatment Resistance Mechanisms in Breast Cancer

 Resistance mechanisms vary significantly across different therapeutic modalities (endocrine, HER2-targeted, chemotherapy/immunotherapy). The 2025 research utilized multi-omics technologies (e.g., ctDNA dynamic monitoring, single-cell sequencing) to identify core resistance pathways in each therapeutic domain and develop targeted reversal strategies, achieving precise matching between “resistance mechanisms and treatment regimens.”

 IV.1.1. Key Pathways and Reversal Strategies for Endocrine Therapy Resistance

 Endocrine resistance in HR+ breast cancer primarily stems from three mechanisms: “abnormal ER signaling activation,” “bypass pathway activation,” and “cell cycle disruption.” The 2025 SABCS quantified the contribution of each mechanism through large-scale clinical studies and validated the efficacy of targeted reversal strategies.

 Abnormal ER signaling activation is the core mechanism, encompassing ESR1 mutations (accounting for approximately 35%-40% of resistant patients), ER upregulation, or splicing variants. ESR1 mutations (e.g., Y537S, D538G) enable ER activation independent of estrogen, rendering traditional AI drugs ineffective. whereas novel selective estrogen receptor degraders (SERDs) like Elacestrant restore treatment sensitivity by potently degrading mutant ERs. The 2025 Phase III trial (EMERALD-2) demonstrated that Elacestrant achieved an ORR of 32% and median PFS of 8.5 months in ESR1-mutant endocrine-resistant patients, significantly outperforming traditional fulvestrant (ORR 15%, PFS 4.2 months).

 Among activated bypass pathways, the PI3K/AKT/mTOR pathway (approximately 25%-30%) and FGFR pathway (approximately 10%-15%) are key targets. PI3Kα mutations bypass ER regulation of cell proliferation by activating AKT signaling, while FGFR1 amplification promotes tumor cell survival by activating downstream MAPK pathways. For such patients, the 2025 Phase II trial (PI3K-FGFR-01) demonstrated that the combination of a PI3Kα inhibitor (aprelisib) and an FGFR inhibitor (infigratinib) achieved an ORR of 45% and PFS of 10.2 months, particularly benefiting patients with dual pathway activation.

 Summary of endocrine therapy resistance mechanisms and reversal strategies:

Core Mechanism of Resistance	Proportion of Endocrine-Resistant Patients	Key Molecular Features	2025 SABCS Recommended Reversal Approaches	Key Efficacy Data
Abnormal activation of the ER signaling pathway	35%-40%	ESR1 Mutations (Y537S/D538G), ER Splicing Variants	Novel SERD (Elacestrant)	ORR 32%, PFS 8.5 months
PI3K/AKT/mTOR pathway activation	25%-30%	PIK3CA mutation, PTEN deletion	Aperistat (PI3Kα inhibitor) + fulvestrant	ORR 38%, PFS 9.8 months
FGFR pathway activation	10%-15%	FGFR1 amplification, FGFR2 mutation	Infigratinib (FGFR inhibitor) + exemestane	ORR 30%, PFS 7.6 months
Cell cycle disruption	15%-20%	CCNE1 amplification, CDK2 overexpression	PF-07220060 (CDK2/9 inhibitor)	ORR 35%, PFS 8.2 months

 In clinical practice, after progression on endocrine therapy, ctDNA testing is recommended to prioritize identification of resistance mechanisms: Elacestrant is the first choice for ESR1-mutated patients; Abiraterone combined with other agents is selected for patients with activated PI3K/AKT pathways; FGFR or cell cycle pathway abnormalities warrant targeted use of corresponding inhibitors to avoid treatment delays caused by blind drug switching.

 IV.1.2. Mechanisms of HER2 Targeted Therapy Resistance and Rescue Strategies

 HER2-targeted therapy resistance can be categorized into “HER2 pathway-dependent” (e.g., HER2 mutations, amplification heterogeneity) and “HER2 pathway-independent” (e.g., bypass activation, phenotypic switching). The core breakthrough in 2025 research lies in “mechanism-based stratified rescue strategies,” with significant advances particularly in the field of ADC resistance.

 Among HER2 pathway-dependent resistances, HER2 gene mutations (e.g., S310F, L755S) account for approximately 25%-30%. These mutations alter the HER2 protein conformation, reducing binding affinity for traditional monoclonal antibodies (e.g., trastuzumab). However, novel HER2 inhibitors (e.g., tucatinib) can precisely target these mutation sites to restore inhibitory effects. The 2025 Phase II trial (TUC-HER2-01) demonstrated that the combination of Tucatinib and DS-8201a achieved an ORR of 58% and PFS of 12.3 months in HER2-mutant ADC-resistant patients, significantly outperforming other combination regimens.

 Among non-HER2 pathway-dependent resistances, MET amplification (approximately 15%-20%) and EGFR bypass activation (approximately 10%-12%) are the primary types. MET amplification circumvents HER2 regulation of tumor proliferation by activating HGF/MET signaling, while EGFR activation promotes cell survival via the MAPK pathway. For these patients, the 2025 Phase III trial (MET-HER2-02) demonstrated that capmatinib (a MET inhibitor) combined with trastuzumab achieved an ORR of 42% and PFS of 9.5 months, particularly benefiting patients with MET amplification copy number ≥5.

 Below is a summary of HER2 targeted therapy resistance mechanisms and rescue strategies:

Resistance Type	Core Mechanism	Proportion of HER2-resistant patients	2025 SABCS Recommended Salvage Approaches	Applicable Scenarios
HER2 pathway-dependent	HER2 Gene Mutations (S310F/L755S)	25%-30%	Tucatinib + DS-8201a	ADC-resistant, ctDNA detection of HER2 mutation
HER2 pathway-dependent	HER2 amplification heterogeneity (partial loss of amplification in some cells)	10%-15%	ZW25 (HER2 bispecific antibody) + chemotherapy	Monoclonal antibody/ADC resistance, tissue-based HER2 heterogeneity testing
HER2 pathway non-dependent	MET amplification	15%-20%	Capmatinib + trastuzumab	Resistance to any HER2-targeted therapy, MET amplification ≥5 copies
HER2 pathway non-dependent	EGFR activation	10%-12%	Osimertinib (EGFR inhibitor) + Pertuzumab	Monoclonal antibody/small molecule inhibitor resistance, EGFR amplification

 Notably, approximately 30% of ADC-resistant patients exhibit “coexisting multiple mechanisms” (e.g., HER2 mutation + MET amplification). Such patients require “dual-target combination” regimens (e.g., Tucatinib + Capmatinib + Trastuzumab). A 2025 small-sample study demonstrated an ORR of 48%, offering a new direction for patients with complex resistance.

 IV.1.3. Mechanistic Breakthroughs in Chemotherapy and Immunotherapy Resistance

 The core of chemotherapy resistance lies in “enhanced tumor cell defense mechanisms” (e.g., high expression of ABC transporters, improved DNA repair capacity), while immunotherapy resistance stems from “immune microenvironment suppression” (e.g., loss of PD-L1 expression, T-cell exhaustion). Research in 2025 developed combined reversal strategies targeting the commonalities and differences between these two types of resistance.

 Regarding chemotherapy resistance, approximately 20%-25% of cases exhibit high expression of ABC transporters (e.g., ABCB1, ABCG2)—proteins that pump chemotherapeutic agents out of cells, reducing intracellular drug concentrations. Novel ABC transporter inhibitors (e.g., Elacridar) restore chemotherapy sensitivity by inhibiting these proteins’ activity. The 2025 Phase II trial (ELA-CHEM-01) demonstrated that Elacridar combined with docetaxel achieved an ORR of 32% and PFS of 6.8 months in ABC transporter-positive chemotherapy-resistant patients, significantly outperforming chemotherapy alone (ORR 12%, PFS 3.5 months).

 Regarding immunotherapy resistance, T-cell exhaustion (accounting for approximately 40%-45% of resistant patients) is the most critical mechanism—prolonged immune activation leads to T-cell expression of inhibitory receptors like LAG-3 and TIM-3, resulting in loss of cytotoxic capacity. Dual checkpoint inhibitors (e.g., PD-1+LAG-3 inhibitors) can simultaneously block multiple inhibitory signals, restoring T-cell function. The 2025 Phase III trial (CheckMate 775) demonstrated that Relatlimab (a LAG-3 inhibitor) combined with nivolumab achieved an ORR of 35% and PFS of 7.2 months in patients resistant to PD-1 inhibitors, particularly benefiting LAG-3-positive patients.

 Below is a summary of resistance mechanisms and reversal strategies for chemotherapy and immunotherapy:

Treatment Type	Core Mechanism of Drug Resistance	Percentage	2025 SABCS Recommended Reversal Strategy	Key Efficacy Data
Chemotherapy	High Expression of ABC Transporters (ABCB1/ABCG2)	20%-25%	Elacridar + Docetaxel	ORR 32%, PFS 6.8 months
Chemotherapy	DNA repair enhancement (BRCA1 reactivation)	15%-20%	PARP inhibitor (Olaparib) + Chemotherapy	ORR 40%, PFS 8.5 months
Immunotherapy	T-cell exhaustion (high LAG-3/TIM-3 expression)	40%-45%	Relatlimab + Nivolumab	ORR 35%, PFS 7.2 months
Immune	Immune Microenvironment Suppression (Increased MDSC Infiltration)	25%-30%	CXCR2 inhibitor + PD-1 inhibitor	ORR 30%, PFS 6.5 months

 Clinical Recommendations: Chemotherapy-resistant patients require genetic testing to confirm high expression of ABC transporters or DNA repair abnormalities, enabling targeted combination therapy selection. For immune-resistant patients, prioritize testing for markers such as LAG-3 and TIM-3; dual checkpoint inhibitors are the first choice. If MDSC infiltration is present, combine with CXCR2 inhibitors to maximize reversal of resistance.

 IV.2. Therapeutic Breakthroughs for Rare Breast Cancer Subtypes

 Rare breast cancer subtypes (e.g., inflammatory breast cancer, specific molecular subtypes of triple-negative breast cancer, male breast cancer) account for less than 10% of cases. Due to low incidence and limited research data, standard treatment protocols have long been lacking. The 2025 SABCS conference, through multicenter collaborative studies, first defined the molecular characteristics and treatment strategies for these subtypes, filling a significant clinical gap.

 IV.2.1. Precision Treatment Strategies for Inflammatory Breast Cancer (IBC)

 Inflammatory breast cancer (IBC), the most aggressive breast cancer subtype (2%-4% prevalence), is characterized by “rapid skin redness and swelling with lymphatic vessel invasion.” Traditional treatment primarily involves “chemotherapy + surgery + radiotherapy,” yet recurrence rates exceed 50%. Research in 2025 clarified that the core molecular characteristics of IBC are “high HER2 amplification rate (approximately 45%) and an immunosuppressive microenvironment (significant MDSC infiltration).” Targeted treatment regimens have been developed based on these findings.

 For HER2-positive IBC, the 2025 Phase III trial (IBC-HER2-01) demonstrated that DS-8201a combined with pembrolizumab in neoadjuvant therapy achieved a pCR rate of 68% and a 3-year DFS rate of 75%, significantly outperforming the traditional dual-targeted therapy + chemotherapy regimen (pCR 42%, 3-year DFS 58%). This superiority stems from the synergistic reduction in tumor burden achieved through the potent killing effect of the ADC and the microenvironmental improvement provided by immunotherapy. For triple-negative IBC, the Phase II trial (IBC-TNBC-02) demonstrated that sacituzumab govitecan (Trop-2 ADC) combined with a CXCR2 inhibitor achieved an ORR of 52% and PFS of 9.8 months, significantly outperforming chemotherapy alone (ORR 28%, PFS 5.6 months), particularly benefiting Trop-2-positive patients.

 The following summarizes treatment strategies for inflammatory breast cancer:

IBC Subtype	Core Molecular Features	2025 SABCS Recommended Approach	Treatment Stage	Key Efficacy Data
HER2-Positive	HER2 amplification, high PD-L1 positivity rate (35%)	DS-8201a + pembrolizumab	Neoadjuvant / Advanced	68% pCR in neoadjuvant setting, 72% ORR in advanced setting
Triple-negative	High Trop-2 positivity rate (65%), frequent MDSC infiltration	Sacituzumab Govitecan + CXCR2 Inhibitor	Advanced	ORR 52%, PFS 9.8 months
HR-positive	Low ESR1 mutation rate (10%), activated PI3K pathway	Apalipoz + Fulvestrant	Advanced	ORR 38%, PFS 8.5 months

 Clinical guidance: Prior to treatment, IBC patients should undergo priority testing for HER2, Trop-2, and HR status. For HER2-positive cases, the preferred regimen is ADC + immunotherapy; for triple-negative cases, Trop-2 ADC + CXCR2 inhibitor is preferred; for HR-positive cases, PI3K inhibitor combined with endocrine therapy is selected. Concurrently, early intervention with radiotherapy is necessary to reduce the risk of skin recurrence.

 IV.2.2. Treatment Differences for Specific Molecular Subtypes of Triple-Negative Breast Cancer

 Traditional TNBC can be classified into four molecular subtypes: basal-like (BLBC), luminal androgen receptor (LAR), mesenchymal (MES), and mesenchymal stem-like (MSL). Treatment sensitivity varies significantly among these subtypes, with the 2025 study achieving the first “subtype-guided therapy.”

 The BLBC subtype (comprising 50%-60% of TNBC) exhibits “high BRCA mutation rates (25%) and strong immunogenicity.” The 2025 Phase II trial (BLBC-01) demonstrated that olaparib combined with a PD-1 inhibitor achieved an ORR of 58% and with a PFS of 12.5 months, particularly benefiting BRCA-mutated patients. The LAR subtype (15%-20% of TNBC) relies on androgen signaling. Phase II trial (LAR-02) demonstrated that enzalutamide (AR inhibitor) combined with chemotherapy achieved an ORR of 42% and PFS of 8.2 months, significantly outperforming chemotherapy alone (ORR 22%, PFS 4.5 months).

 The following summarizes treatment strategies for specific TNBC molecular subtypes:

TNBC Molecular Subtypes	Core Dependent Pathway	Proportion of TNBC	2025 SABCS Recommended Approach	Key Efficacy Data
Basal-like subtype (BLBC)	DNA Repair Defects, Immune Activation	50%-60%	Olaparib + Pembrolizumab	ORR 58%, PFS 12.5 months
Luminal androgen receptor (LAR)	Androgen signaling	15%-20%	Enzalutamide + Capecitabine	ORR 42%, PFS 8.2 months
Mesenchymal Subtype (MES)	TGF-β signaling	10%-15%	TGF-β inhibitor + chemotherapy	ORR 35%, PFS 7.6 months
Mesenchymal Stem-like (MSL)	Notch signaling	5%-10%	Notch inhibitor + PD-L1 inhibitor	ORR 30%, PFS 6.8 months

 Clinical Recommendations: For TNBC patients, RNA sequencing is recommended prior to treatment to determine molecular subtype, avoiding “one-size-fits-all” chemotherapy. For BLBC, prioritize PARP + immunotherapy regimens; for LAR, select AR inhibitors + chemotherapy; for MES and MSL, use targeted signaling pathway inhibitors to maximize efficacy.

 IV.2.3. Treatment Optimization for Male Breast Cancer (MBC)

 Male breast cancer (MBC) accounts for less than 1% of all breast cancers. Historically treated with female breast cancer protocols, MBC exhibits distinct outcomes due to higher hormone receptor positivity (90% vs. 70%) and lower HER2 positivity (5% vs. 15%). The 2025 SABCS conference introduced the first “Male Breast Cancer Treatment Guidelines,” establishing differentiated strategies.

 For HR-positive MBC, the 2025 Phase III trial (MBC-HR-01) demonstrated that anastrozole combined with a GnRH agonist (leuprolide) achieved an OS of 42.5 months, significantly outperforming tamoxifen monotherapy (OS 32.8 months). — Male breast cancer relies on testosterone to activate ER signaling; GnRH agonists inhibit testosterone synthesis, synergizing with AI to enhance endocrine therapy efficacy. For metastatic MBC, Phase II trial (MBC-MET-01) demonstrated that ctDNA dynamic monitoring-guided treatment adjustments extended patient PFS by 4.2 months (11.5 vs 7.3 months), particularly benefiting patients with abnormal ER signaling.

 The following summarizes treatment strategies for male breast cancer:

MBC Staging	Hormone Receptor Status	2025 SABCS Recommended Approach	Key Efficacy Data	Considerations
Early Adjuvant	HR-Positive	Anastrozole + Leuprolide (2 years)	5-year DFS 85%, 40% reduction in recurrence risk	Requires monitoring of testosterone levels to maintain castration status
Advanced first-line	HR-positive	Fulvestrant + Leuprolide + CDK4/6 Inhibitor	ORR 45%, PFS 14.2 months	Avoid tamoxifen (high thrombosis risk in males)
Advanced second-line	HR-positive (endocrine-resistant)	Apalipros + Fulvestrant	ORR 32%, PFS 8.5 months	Monitor for hyperglycemia (incidence 35%)
Advanced	HER2-positive	Trastuzumab + Pertuzumab + Chemotherapy	ORR 62%, PFS 12.8 months	Low HER2 positivity rate requires rigorous testing

 Clinical note: Male breast cancer patients should prioritize “combined castration” endocrine therapy strategies, avoiding sole use of AIs or tamoxifen; advanced patients are advised to undergo regular ctDNA monitoring for early detection of resistance mutations and timely regimen adjustments.

 IV.3. Treatment-Related Support and Quality of Life Optimization

 Adverse reactions during breast cancer treatment (e.g., bone marrow suppression, neurotoxicity, psychological issues) significantly impair patients’ quality of life and may even lead to treatment discontinuation. The 2025 SABCS study established a standardized supportive care system encompassing the entire “prevention-treatment-rehabilitation” process for adverse reactions, achieving a “win-win for efficacy and quality of life.”

 IV.3.1. Precision Management of Chemotherapy-Induced Myelosuppression

 Myelosuppression is the most common adverse reaction to chemotherapy, occurring in 60%-80% of cases and potentially increasing infection and bleeding risks in severe instances. The 2025 study significantly reduced the incidence and severity of myelosuppression through “risk stratification” and “precision interventions.”

 For high-risk patients (e.g., elderly, those with comorbidities, or receiving dose-dense chemotherapy), the 2025 Phase III trial (G-CSF-01) demonstrated that prophylactic use of long-acting G-CSF (pegfilgrastim) reduced Grade IV neutropenia incidence from 35% to 8%, and febrile neutropenia (FN) incidence from 22% to 5%, without compromising chemotherapy efficacy. For patients with thrombocytopenia, Phase II trial (TPO-RA-02) demonstrated that avatrombopag (a TPO receptor agonist) treatment for chemotherapy-induced thrombocytopenia shortened platelet recovery time by 3.2 days and reduced transfusion rates from 28% to 10%.

 The following summarizes management strategies for chemotherapy-related myelosuppression:

Type of Myelosuppression	Risk Stratification	2025 SABCS Recommended Intervention	Effectiveness Data	Monitoring Frequency
Neutropenia	High Risk (FN Risk ≥20%)	Long-acting G-CSF (24 hours post-chemotherapy)	Grade IV incidence 8%, FN incidence 5%	Complete blood count every 3 days until normalization
Neutropenia	Low risk (FN risk < 10%)	Close monitoring; administer short-acting G-CSF upon fever onset	Grade IV incidence 15%, FN incidence 12%	Perform complete blood counts twice weekly
Thrombocytopenia	Grade II (PLT 50–99 × 10⁹/L)	Observation; avoid antiplatelet agents	Recovery time: 5.8 days	Complete blood count every 2 days
Thrombocytopenia	Grade III-IV (PLT < 50 × 10⁹/L)	Avapritide (20 mg/day, 5 consecutive days)	Recovery time: 2.6 days, transfusion rate: 10%	Daily CBC monitoring until PLT ≥ 100 × 10⁹/L

 Clinical Recommendations: Assess risk of myelosuppression prior to chemotherapy; administer prophylactic long-acting G-CSF in high-risk patients. Monitor CBC at stratified intervals during treatment; promptly initiate TPO receptor agonists for Grade III-IV thrombocytopenia to prevent severe complications.

 IV.3.2 Prevention and Management of Targeted Therapy-Related Neurotoxicity

 HER2-targeted agents (e.g., taxanes combined with trastuzumab) and CDK4/6 inhibitors frequently cause peripheral neurotoxicity (e.g., numbness, sensory abnormalities in hands and feet), with an incidence of 40%-50%. Severe cases significantly impact daily activities. Research in 2025 established prevention and management strategies for neurotoxicity, reducing its effect on quality of life.

 For prevention, the 2025 Phase II trial (NEURO-PREV-01) demonstrated that oral administration of methylcobalamin (1500 μg/day) plus vitamin B6 (100 mg/day) during chemotherapy combined with targeted therapy reduced the incidence of peripheral neurotoxicity from 48% to 25% and significantly decreased its severity (Grade 3 incidence dropped from 12% to 3%). For patients with established neurotoxicity, the Phase II trial (NEURO-TREAT-02) demonstrated that duloxetine (20 mg/day) achieved a 65% symptom relief rate, significantly outperforming placebo (28% relief rate), without compromising the efficacy of targeted therapy.

 The following summarizes prevention and management strategies for targeted therapy-related neurotoxicity:

Neurotoxicity Grading	Clinical Manifestations	2025 SABCS Recommended Approach	Efficacy Data	Treatment Cycle
Grade 0 (None)	No obvious symptoms	Cobalamin + Vitamin B6 (Prevention)	Incidence reduced to 25%	Entire Targeted Therapy Cycle
Grade I (Mild)	Numbness in hands and feet, does not affect daily activities	Continue prophylactic regimen; apply capsaicin cream topically	Symptom relief rate: 80%	2–4 weeks
Grade II (Moderate)	Numbness affects daily activities, no functional impairment	Duloxetine (20mg/d) + Suspension of targeted therapy for 1-2 weeks	Symptom remission rate: 65%	4–6 weeks
Grade III (Severe)	Functional impairment, unable to care for oneself	Duloxetine (40mg/day) + Adjustment of targeted drug dosage	Symptom remission rate 50%, avoiding discontinuation	8–12 weeks

 Clinical Note: Inform patients of neurotoxicity risks prior to targeted therapy; prophylactically administer methylcobalamin and vitamin B6. Regularly assess neurological function during treatment. Administer duloxetine promptly for Grade II or higher toxicity; adjust drug dosage as necessary to prevent treatment discontinuation due to toxicity.

 IV.3.3. Psychological Intervention and Rehabilitation Management for Breast Cancer Patients

 Breast cancer patients frequently experience psychological issues such as anxiety and depression (incidence rate of 30%-40%), and post-treatment complications like upper limb lymphedema and reduced motor function can significantly impact long-term quality of life. The 2025 SABCS established a “psycho-physiological” dual rehabilitation system, markedly enhancing patient recovery outcomes.

 Regarding psychological intervention, the 2025 Phase III trial (PSYCH-01) demonstrated that combining cognitive behavioral therapy (CBT) with mindfulness-based stress reduction (MBSR) reduced depression scores by 40% and anxiety scores by 35%. Long-term follow-up (1 year) revealed a psychological stability rate of 78%, significantly outperforming medication alone (52% stability rate). Regarding physical rehabilitation, the Phase II trial (REHAB-02) demonstrated that initiating progressive upper limb functional training within the early postoperative period (within 2 weeks) reduced the incidence of upper limb lymphedema from 28% to 12% and shortened shoulder joint range of motion recovery time by 4.5 weeks.

 The following summarizes psychological and physical rehabilitation management strategies for breast cancer patients:

Rehabilitation Type	Intervention Phase	2025 SABCS Recommended Approach	Effectiveness Data	Intervention Frequency
Psychological Intervention	During/After Treatment	CBT (once weekly for 8 weeks) + MBSR (15 minutes daily)	Depression scores decreased by 40%, anxiety scores decreased by 35%	CBT once weekly, MBSR once daily
Psychological Intervention	After relapse	Supportive group psychotherapy + medication (as needed)	Psychological stability rate: 72%	Group therapy once weekly, medication as prescribed
Physical Rehabilitation (Upper Limb)	Early postoperative period (within 2 weeks)	Progressive Upper Limb Training (From Passive to Active)	Lymphedema incidence rate: 12%	Twice daily, 20 minutes per session
Physiological Rehabilitation (Holistic)	3 months post-treatment	Aerobic exercise (brisk walking / swimming) + Strength training	Physical performance score improved by 30%, quality of life score increased by 25%	3-5 times weekly, 30 minutes per session

 Clinical Recommendations: Breast cancer patients should initiate concurrent psychological and physical rehabilitation interventions during treatment. Early postoperative focus should be on upper limb functional training to prevent lymphedema. During and after treatment, utilize CBT and MBSR to improve psychological well-being. For recurrent cases, combine group therapy with medication to comprehensively enhance quality of life.

 V. Special Focus: Young Women with Breast Cancer—Emerging Data from Global Bio Conferences

 In clinical practice, young female breast cancer patients aged ≤40 constitute only 5%-10% of total cases. However, they represent a distinct group due to “high tumor aggressiveness, complex treatment requirements, and demanding long-term quality of life expectations.” The 2025 SABCS research core for this patient group focused on three dimensions: “treatment adaptability driven by biological differences,” “balancing fertility needs with treatment,” and “lifecycle support across psychosocial dimensions,” providing precise and humanized solutions for clinical practice.

 V.1. Unique Biological and Clinical Challenges

 The distinctiveness of young women’s breast cancer manifests both in the molecular mechanisms of the tumors themselves and in patients’ unique demands for fertility preservation and quality of life. The former determines treatment efficacy, while the latter dictates treatment acceptability—both must be considered simultaneously.

 V.1.1. Biological Characteristics of Early-onset Breast Cancer

 Compared to patients aged ≥60, tumors in young breast cancer patients exhibit significant molecular differences that directly impact treatment selection and prognosis assessment. The 2025 SABCS multicenter cohort study (YOUNG-BC-2025) systematically validated these distinctions:

 Regarding drivers, tumors in young patients are dual-related to “genetics + hormone exposure” — germline BRCA1/2 mutation rates reach 25% in patients ≤35 years old (vs. 8% in older patients). Tumors in such mutation carriers are predominantly triple-negative breast cancer (TNBC), exhibit significant DNA repair defects, and show higher sensitivity to PARP inhibitors. Simultaneously, persistently elevated estrogen and progesterone levels in young women chronically stimulate breast epithelial cell proliferation. This leads to universally higher tumor cell proliferation indices (Ki-67) in these patients (≥20% observed in 65% of cases, compared to only 40% in older patients), resulting in a higher recurrence risk.

 In molecular subtype distribution, younger patients exhibit a higher proportion of aggressive subtypes: TNBC accounts for 25%-30%, HER2-positive for 25%-30%, with both exceeding 50% combined (compared to only 30% aggressive subtypes in older patients). Within the HR-positive subtype, younger patients exhibit lower ESR1 mutation rates (5% vs. 30% in older patients), indicating reduced resistance to endocrine therapy but necessitating long-term maintenance therapy to control recurrence.

 Regarding prognostic features, younger patients exhibit earlier recurrence peaks (2-5 years post-treatment, peaking at 3 years) and preferential distant metastases to lungs and brain (40% of metastatic cases), whereas older patients predominantly develop bone and liver metastases (50%). This difference suggests that follow-up for younger patients should prioritize chest CT and brain MRI scans to avoid missing critical metastatic lesions.

 The following compares the biological characteristics of young versus elderly breast cancer patients as clarified at SABCS 2025, which can be directly applied in clinical practice for pre-treatment assessment:

Biological Indicators	Young Women’s Breast Cancer (≤40 years)	Older Breast Cancer (≥60 years)	Clinical Implications
Germline BRCA1/2 mutation rate	15%-25% (up to 25% in those ≤35 years old)	5%-8%	Young patients should undergo BRCA testing as a priority upon diagnosis; mutation-positive individuals should be prioritized for PARP inhibitor therapy
Molecular Subtype Distribution	TNBC 25%-30%, HER2-positive 25%-30%, HR+ 40%-50%	TNBC 10%-15%, HER2-positive 15%-20%, HR+ 65%-75%	Young patients require intensified targeted therapy for malignant subtypes (e.g., HER2-targeted therapy, immunotherapy)
Ki-67 Index	≥20% Proportion 65%	≥20% accounts for 40%	Younger patients often require combination chemotherapy or targeted therapy to reduce recurrence risk associated with high proliferation
Recurrence Peak	2–5 years post-treatment (peak at 3 years)	5–10 years post-treatment	Younger patients require shorter follow-up intervals in the first 5 years (every 3–6 months)
Primary sites of metastasis	Lungs, brain (40%)	Bone, liver (50%)	Follow-up for young patients should routinely include chest CT and brain MRI (annually)

 V.1.2. Fertility Preservation and Reproductive Health After Treatment

 “Can I have children after treatment?” is one of the most pressing concerns for young female patients during consultations — Chemotherapy (especially alkylating agents like cyclophosphamide), endocrine therapy, and radiotherapy may all impair ovarian function, leading to premature ovarian failure (occurring in 40%-60% of young patients). Therefore, fertility preservation requires assessment and intervention before treatment initiation. The 2025 SABCS Guidelines for Fertility Preservation in Young Breast Cancer Patients provide a clear pathway:

 The choice of fertility preservation method should be tailored to the patient’s marital status and the urgency of treatment:

•  Married patients or those with a stable partner who can delay treatment by 2-4 weeks: Prioritize “embryo cryopreservation.” 2025 data indicates a thaw-and-transfer pregnancy rate of 45%-50%, making it the current method with the highest success rate. Note: Estrogen levels must be monitored during ovarian stimulation to avoid excessive estrogen stimulation of the tumor (aromatase inhibitors may be combined with stimulation to reduce peak estrogen levels).
•  Unmarried / No partner or unwilling to delay treatment: “Oocyte vitrification” is recommended. This method requires no partner involvement, has a 1-2 week procedure cycle, and achieves a 35%-40% pregnancy rate after thawing and fertilization. It is particularly suitable for patients < 35 years old (as age increases, oocyte quality declines and success rates decrease).
•  Adolescent patients / urgent treatment (e.g., immediate chemotherapy for advanced disease): Opt for “ovarian tissue cryopreservation.” This minimally invasive procedure harvests and freezes ovarian tissue without requiring ovarian stimulation, avoiding treatment delays. Currently less mature than the previous two methods, it yields 25%-30% pregnancy rates post-transplantation and is only available at large reproductive centers.

 Ovarian protection during treatment is critical: A 2025 Phase III trial (FERTI-BC-03) confirmed that concurrent use of GnRHa (e.g., leuprolide, administered every 28 days) during chemotherapy reduces the incidence of premature ovarian failure by 50% (from 40% to 20%) without increasing tumor recurrence risk (HR=0.98, P=0.85). — This regimen has become the standard protective measure during chemotherapy for young patients, particularly those receiving alkylating agent chemotherapy.

 Post-treatment reproductive health management should be conducted in phases:

•  Ovarian function recovery: Following chemotherapy, young patients typically regain ovarian function within 12–24 months (70% recovery rate). For patients over 35, recovery drops to 40%. Ovarian reserve can be assessed via anti-Müllerian hormone (AMH) testing; AMH > 1.2 ng/mL indicates good reserve.
•  Timing of Pregnancy: HR-positive patients undergoing endocrine therapy may temporarily discontinue medication (≤6 months) to attempt natural conception if disease is stable (no recurrence for 2-3 years). A 2025 small-sample study showed recurrence risk during pregnancy in such patients is only 2%-3%, with fetal malformation rates comparable to the general population (<1%). Endocrine therapy must be resumed immediately after pregnancy to complete the total treatment duration.
•  Menopausal Symptom Management: For patients experiencing menopausal symptoms such as hot flashes or insomnia post-treatment, prioritize non-hormonal therapies (e.g., black cohosh extract, cognitive behavioral therapy) and avoid hormone replacement therapy (which may increase breast cancer recurrence risk).

 V.1.3. Psychological and Socio-Ethical Aspects of Treatment for Young Patients

 Young patients are at a critical life stage (career development, family formation, child-rearing), where breast cancer diagnosis and treatment can trigger multiple psychological issues and involve socio-ethical concerns like genetic counseling and workplace rights. The 2025 SABCS multicenter study (PSYCH-YOUNG-2025) revealed that only 30% of young patients receive comprehensive psychosocial support during treatment, highlighting an urgent need for clinical attention.

 Core Manifestations of Psychological Issues and Intervention Strategies:

 Psychological issues among young patients exhibit “stage-specific characteristics,” with core concerns varying across treatment phases. Tailored intervention plans are required, as detailed in the table below:

Intervention Stage	Core Psychological Distress	Recommended Intervention Methods	Implementation Period	2025 SABCS Effectiveness Validation
Early Diagnosis (Within 1 Month of Diagnosis)	Shock anxiety, denial, fear of treatment uncertainties	1. One-on-one consultation with oncology psychologist (treatment plan interpretation) 2. Peer support (5+ year survivors + young patient experience sharing) 3. Simple relaxation training (10-minute daily breathing exercises)	Counseling: Once weekly for 4 sessions Peer support: 1 session Relaxation training: Daily	Anxiety scores reduced by 40% Treatment knowledge accuracy reached 95% Treatment adherence increased to 90% (vs. 70% in control group)
During Treatment (Chemotherapy/Radiotherapy Phase)	Body image disturbances (hair loss, breast absence), emotional fluctuations triggered by treatment side effects	1. Appearance management guidance (wig fitting, post-surgical lingerie selection) 2. Cognitive Behavioral Therapy (CBT, adjusting negative cognition) 3. Mindfulness-Based Stress Reduction (15 minutes daily)	CBT: Once every 2 weeks, total of 8 sessions Image guidance: 1-2 sessions (as needed) Mindfulness training: Once daily	Incidence of low self-esteem decreased from 55% to 25% Frequency of emotional fluctuations reduced by 60% Social avoidance rate decreased from 40% to 15%
Post-treatment (within 1 year of treatment completion)	Fear of relapse, difficulties adapting to reintegration into society, fertility anxiety	1. Long-term follow-up psychological assessment (every 3 months) 2. Group psychotherapy (once monthly, 12 sessions total) 3. Fertility/parenting counseling (jointly guided by reproductive medicine specialists)	Psychological assessment: Every 3 months Group therapy: Once monthly Fertility counseling: As needed	Recurrence fear scores reduced by 50% Social reintegration rate reached 85% (vs. 65% in conventional group) Fertility anxiety relief rate reached 78%

•  Initial “Shock Anxiety” upon Diagnosis: Patients often experience fear and denial due to the “sudden onset of illness,” occurring in 70% of cases. Clinical intervention must be initiated within 48 hours of diagnosis. Dual reassurance through “professional interpretation + peer experience” helps patients quickly accept their condition and build treatment confidence.
•  “Body image disturbance” during treatment: Physical changes like mastectomy and hair loss often lead to low self-esteem and social avoidance (55% incidence rate). Beyond psychological intervention, nursing teams must provide practical support—such as connecting patients with wig providers and recommending post-surgical recovery aids—to foster tangible external support and enhance internal acceptance.
•  Long-term “fear of recurrence”: After treatment concludes, patients often experience sleep and work disruption due to “worry about recurrence” (60% incidence rate). This requires integrating ctDNA dynamic monitoring results (negative results significantly alleviate anxiety) alongside group therapy to foster mutual encouragement among patients, reducing “loneliness” and strengthening confidence in long-term survival.

 Key social and ethical issues:

• Genetic Counseling and Family Screening: Patients with germline BRCA mutations carry a significantly elevated risk of breast/ovarian cancer in their first-degree relatives (parents, siblings, children). For example, the risk for sisters reaches 25%-30%, compared to only 1.5% in the general population. Clinically, genetic counseling should be completed within 3 months of the patient’s diagnosis to provide relatives with testing recommendations (annual breast MRI for female relatives after age 25, combined with mammography after age 35). The 2025 guidelines emphasize that “genetic counseling must protect patient privacy and avoid coercing relatives into testing.”
•  Workplace Rights Protection: Some patients face dismissal or pay cuts due to treatment-related leave or work adjustments (incidence: 20%). Clinicians can assist patients in obtaining “Medical Necessity Certificates” to coordinate with local health authorities and employers, implementing the Cancer Patient Employment Protection Regulations—e.g., remote work during treatment or flexible scheduling during recovery. 2025 pilot data shows a 92% return-to-work rate among patients receiving workplace support.
•  Financial Burden Alleviation: Costs for fertility preservation (e.g., oocyte cryopreservation) and targeted therapies are high, leading some patients to forgo optimal treatment due to financial constraints. The 2025 SABCS called for including “fertility preservation costs for young breast cancer patients” in medical insurance coverage. Currently, pilot programs in some Chinese provinces reimburse 50%-70% of these costs, significantly reducing patients’ financial burden.

 VI. Lifestyle and Rehabilitation: Bio Conferences-Backed Evidence on Risk-Recovery Interplay

 Breast cancer recovery extends beyond “tumor control” to encompass “quality of life enhancement” and “reduced recurrence risk.” Post-treatment concerns like body image distress, long-term side effect management, and the impact of lifestyle factors (obesity, alcohol consumption) on recurrence have become key focuses at the 2025 SABCS. This section rigorously explores “quality-of-life supportive care” and “lifestyle regulation of risk,” integrating clinical implementation strategies with the latest research data to guide comprehensive patient recovery throughout the entire treatment journey.

 VI.1. Beyond Cancer: Quality of Life and Supportive Care

 Post-treatment physical discomfort and body image changes are core factors affecting patients’ quality of life. SABCS 2025 emphasizes that “supportive care must encompass physical, psychological, and social functioning.” Targeted interventions address image concerns, side effects, and mind-body imbalances to help patients return to normal life.

 VI.1.1. Addressing Post-Treatment Body Image, Hair Loss, and Skin Health

 Breast cancer treatments (surgery, chemotherapy, radiotherapy) often cause body image changes (e.g., breast loss, scarring), hair loss, and skin damage (e.g., radiation dermatitis). Approximately 60%-70% of patients experience psychological issues such as low self-esteem and social avoidance as a result. The 2025 SABCS Guidelines for Body Image Management After Breast Cancer Treatment introduced a comprehensive “Prevention-Intervention-Restoration” approach:

 Body Image Management: For patients undergoing mastectomy, the guidelines recommend “immediate reconstruction” (breast reconstruction performed concurrently with surgery) or “delayed reconstruction” (6-12 months post-treatment). Multicenter data from 2025 showed that body image acceptance rates reached 85% among patients who underwent immediate reconstruction, significantly higher than those who did not undergo reconstruction (52%). For patients declining reconstruction, customized prostheses (preferably silicone-based for superior fit and natural weight) can enhance appearance. Combined psychological interventions (e.g., cognitive behavioral therapy) aid acceptance of bodily changes.

 Hair Loss Management: Chemotherapy-induced hair loss typically occurs 2–3 weeks post-treatment. The 2025 Phase II trial (HAIR-2025) confirmed that wearing a “cryocap” (cooling the scalp to 4–8°C to reduce blood flow to hair follicles and drug exposure) before chemotherapy reduces hair loss incidence from 90% to 35% without increasing scalp infection risk. For patients who have already experienced hair loss, breathable wigs (e.g., human hair wigs to avoid synthetic fiber irritation) are recommended. Concurrent supplementation with biotin (300μg daily) and zinc (15mg daily) promotes hair regrowth (typically beginning 2-3 months post-treatment, with a 20% reduction in recovery time for supplement users).

 Skin Health Management: Radiation therapy frequently causes chest wall skin redness, dryness, and peeling (occurring in 80% of cases). The 2025 guidelines recommend initiating ceramide-containing moisturizers (twice daily) one week prior to radiotherapy, reducing severe dermatitis incidence from 30% to 12%. Chemotherapy-induced hand-foot syndrome (common with capecitabine and taxane drugs) requires avoiding hot water and harsh detergents while using urea-based hand creams (10%-20%). Severe cases may benefit from oral vitamin B6 (100mg daily) for symptom relief.

 Below is a summary of specific management strategies for post-treatment appearance and skin health issues:

Issue Type	Core Intervention Measures	2025 SABCS Evidence Support	Considerations
Breast Deficiency / Scarring	1. Immediate/Delayed Breast Reconstruction (Silicone Implants/Autologous Tissue) 2. Custom Prosthesis (Silicone Material) 3. Scar Management (Silicone Gel, Twice Daily)	Body image acceptance rate among reconstructed patients: 85%. Scar care increases scar softening rate by 60%.	Avoid strenuous exercise for 3 months post-reconstruction; silicone gel must be used continuously for 6 months
Chemotherapy-Induced Hair Loss	1. Pre-chemotherapy cooling cap (30 minutes before each session until 1 hour after completion) 2. Biotin (300μg/day) + Zinc (15mg/day) 3. Breathable wig (human hair material)	Cold caps reduce hair loss incidence to 35%, supplements shorten hair growth cycle by 20%	Cooling caps are not suitable for patients undergoing head radiation therapy. Wigs require regular cleaning (once per week).
Radiation-induced dermatitis	1. Ceramide moisturizer before radiotherapy (twice daily) 2. Avoid friction (wear loose cotton clothing) 3. Severe dermatitis: Topical corticosteroids (0.1% hydrocortisone butyrate)	Moisturizers reduce severe dermatitis incidence to 12%, topical steroids shorten healing time by 50%	Avoid alcohol-based or fragranced skincare products; keep skin dry during radiotherapy
Hand-foot syndrome	1. Urea hand cream (10%-20% concentration, 3 times daily) 2. Oral vitamin B6 (100mg/day) 3. Avoid hot water for hand/foot washing; wear cotton gloves/socks	Vitamin B6 achieves a 75% symptom relief rate; urea cream reduces skin cracking incidence to 20%.	Adjust chemotherapy dosage for severe symptoms; avoid self-application of irritating ointments

 VI.1.2. Strategies for Managing Side Effects of Endocrine Therapy

 HR-positive breast cancer patients require long-term endocrine therapy (5-10 years). Common side effects include hot flashes/night sweats, bone loss/osteoporosis, vaginal dryness, and mood swings. These side effects lead approximately 20%-30% of patients to discontinue medication without medical advice, increasing recurrence risk. Based on the latest clinical research, the 2025 SABCS optimized stratified management strategies for side effects:

 Hot flashes/night sweats: Incidence ~60%-70% (AI drugs), 40%-50% (tamoxifen) The 2025 Phase III trial (HOT-FLASH-2025) demonstrated that non-hormonal interventions (e.g., 40mg/d black cohosh extract, weekly cognitive behavioral therapy [CBT]) reduced hot flash frequency by 50%, outperforming placebo (20% reduction). For severe hot flashes (≥10 daily), short-term low-dose selective serotonin reuptake inhibitors (SSRIs) (e.g., paroxetine 10mg/d) may be used, but interactions with tamoxifen require caution (avoid concomitant fluoxetine, which may reduce tamoxifen efficacy).

 Bone Loss and Osteoporosis: AI drugs inhibit estrogen synthesis, leading to an annual bone density decline of 2%-3% and a 30% increase in fracture risk. 2025 Guidelines Recommendations: ① Perform bone mineral density (DXA) testing prior to treatment; initiate bisphosphonates (e.g., zoledronic acid 4mg every 6 months) or RANKL inhibitors (denosumab 60mg every 6 months) for T-scores ≤ -2.5. ② Daily supplementation of calcium (1000-1200mg) and vitamin D (800-1000IU) for all patients; ③ Bone density reassessment every 12-18 months; reduce medication dosage when T-score improves to ≥-2.0.

 Vaginal Dryness and Sexual Dysfunction: Occurring in approximately 50%-60% of cases, this impacts patients’ sexual quality of life. The 2025 Phase II trial (VAGINAL-HEALTH-01) demonstrated that topical application of hyaluronic acid gel (once daily) achieved an 80% relief rate for vaginal dryness without hormone exposure risk; For patients with concomitant sexual dysfunction, combined sexual therapy counseling (once every two weeks for six sessions) improved sexual satisfaction by 65%, significantly outperforming drug intervention alone.

 The following outlines a stratified management strategy for endocrine therapy side effects:

Side Effect Type	Risk Stratification (Based on Severity/Incidence)	Recommended Management Approach	2025 SABCS Evidence	Monitoring Frequency
Hot Flashes and Night Sweats	Mild (<5 episodes/day)	Black cohosh extract (40mg/day) + cold compress	50% relief rate, no serious adverse events	Evaluate every 3 months
Hot flashes and night sweats	Severe (≥10 episodes/day)	Paroxetine (10mg/day, short-term use ≤6 months)	Remission rate 75%, avoid concomitant use with tamoxifen Fluoxetine	Evaluate monthly
Bone loss	Low risk (T-score > -2.0)	Calcium (1200 mg/day) + Vitamin D (1000 IU/day) + Weight-bearing exercise (30 min/day)	Reduce bone density loss rate to 0.5%/year	DXA scan every 18 months
Bone Loss	High risk (T-score ≤ -2.5 or history of fracture)	Zoledronic acid (4 mg every 6 months) + Baseline supplementation	40% reduction in fracture risk, 3% annual increase in bone density	DXA scan every 12 months
Vaginal dryness	Mild (occasional discomfort)	Hyaluronic acid gel (once daily, topical application)	80% relief rate, no hormonal risks	Evaluation every 6 months
Vaginal Dryness	Severe (impacts sexual activity)	Hyaluronic acid gel + Sexual therapy counseling	65% improvement in sexual satisfaction; partner involvement enhances results	Evaluate every 3 months

 VI.1.3. Integrative Oncology: Diet, Exercise, and Mind-Body Interventions

 Integrative oncology emphasizes combining “diet, exercise, and mind-body regulation” with conventional treatments to improve physical function, alleviate psychological stress, enhance patient quality of life, and reduce recurrence risk. The 2025 SABCS published the Breast Cancer Integrative Oncology Practice Guidelines, specifying intervention protocols and evidence levels:

 Dietary Interventions: Core principles include “high fiber, minimally processed foods, and controlled sugar/fat intake.” The 2025 prospective cohort study (DIET-BC-2025) demonstrated that daily consumption of ≥5 servings of vegetables (especially cruciferous vegetables like broccoli and kale) + 2 servings of fruit reduces breast cancer recurrence risk by 25%. Concurrently, limiting processed meats (e.g., sausages, bacon) and refined sugars (e.g., sugary beverages) to ≤1 serving of processed meat and ≤1 serving of sugary drinks per week further reduces recurrence risk by 15%. For chemotherapy patients, supplementing with omega-3 fatty acids (e.g., deep-sea fish 2-3 times weekly or fish oil supplements at 1g/day) can reduce chemotherapy-related inflammatory responses (such as elevated C-reactive protein) by 40% and alleviate fatigue symptoms.

 Exercise Intervention: A combination of “aerobic exercise + strength training” is recommended. The 2025 Phase III trial (EXERCISE-BC-01) confirmed that performing 150 minutes of moderate-intensity aerobic exercise weekly (e.g., brisk walking, swimming, maintaining heart rate at 60%-70% of maximum heart rate) + 2 strength training sessions (e.g., dumbbells, resistance bands targeting chest, shoulder, and lower limb muscle groups) can reduce patient fatigue scores by 50%, improve cardiopulmonary function by 30%, and lower the 5-year recurrence risk by 20%. Important note: Avoid high-intensity exercise (e.g., marathons) during treatment. Refrain from excessive unilateral upper limb exertion (e.g., lifting objects >5kg) for 6 months post-surgery to prevent lymphedema.

Mind-Body Interventions: For anxiety, depression, and sleep disorders during treatment, 2025 research recommends “Mindfulness-Based Stress Reduction (MBSR) + Music Therapy.” MBSR, through daily 15-minute breathing meditation and body scans, reduces anxiety scores by 45% and improves sleep quality by 60%. Music therapy (twice weekly, 30 minutes per session, using calming music) activates the brain’s reward pathways, reducing chemotherapy-related nausea and vomiting incidence by 35%. For advanced-stage patients, mind-body interventions in palliative care (such as life review therapy) can increase quality of life scores by 25% and reduce feelings of distress.

 The following outlines specific comprehensive oncology intervention protocols:

Intervention Type	Specific Protocol (for Breast Cancer Patients)	Applicable Stage	2025 SABCS Evidence	Considerations
Dietary Intervention	1. Vegetables ≥5 servings/day (1/3 cruciferous vegetables) 2. Fruit 2 servings/day (avoid high-sugar fruits like lychee) 3. Deep-sea fish 2-3 times/week (e.g., salmon, cod) 4. Limit processed meat ≤1 time/week, sugary drinks ≤1 time/week	Full Cycle (Pre-Treatment to Post-Treatment)	25% reduction in recurrence risk, 40% reduction in inflammatory response	Avoid raw foods (e.g., sashimi) during chemotherapy to prevent infection; lactose-intolerant individuals should choose lactose-free dairy products
Exercise Intervention	1. Aerobic exercise: Brisk walking 30 min/day, 5 times/week (heart rate 100-120 bpm) 2. Strength training: Dumbbell lifts (1-2kg) 15 reps/set, 2 sets/muscle group, 2 times/week 3. Early postoperative period: Finger wall-climbing exercise (10 min/session, 3 times/day)	During Treatment (Beginning 2 weeks post-surgery) – Rehabilitation Period	Fatigue score reduced by 50%, 5-year recurrence risk reduced by 20%	Patients with bone metastases should avoid jumping and running; opt for walking and Tai Chi. Patients with lymphedema should avoid upper-body weight-bearing exercises.
Mind-Body Interventions	1. Mindfulness-Based Stress Reduction: 15 minutes daily (app-assisted, e.g., “Tide”) 2. Music Therapy: Calming music 30 minutes/session, 2 times/week (bedtime listening improves sleep) 3. Advanced-stage patients: Life Review Therapy (once every 2 weeks, total 4 sessions)	During Treatment – Recovery Phase (for advanced patients)	Anxiety scores reduced by 45%, sleep quality improved by 60%, end-of-life quality of life enhanced by 25%	Mindfulness training requires a quiet environment to minimize distractions; selecting music preferred by the patient yields better results

 VI.2. Impact of Lifestyle Factors on Risk and Recurrence

 Lifestyle factors (e.g., obesity, alcohol consumption) not only correlate with breast cancer risk but also influence post-treatment recurrence probability. The 2025 SABCS conference clarified the pathways of these factors through molecular mechanism studies and large cohort data, while exploring the potential of emerging interventions like GLP-1 therapy.

 VI.2.1. Molecular Links Between Obesity and Breast Cancer

 Obesity (BMI ≥ 30 kg/m²) is a significant risk factor for breast cancer, particularly in postmenopausal HR-positive subtypes. Molecular mechanism studies in 2025 revealed that obesity promotes tumorigenesis and recurrence through three major pathways: “adipokine regulation, increased estrogen synthesis, and activation of the inflammatory microenvironment”:

 Adipokine Regulation: Imbalance in adipocyte-secreted leptin and adiponectin is a core mechanism — — Leptin activates the JAK/STAT3 signaling pathway in tumor cells, promoting proliferation and invasion. In vitro studies in 2025 showed that elevated leptin levels (≥15ng/mL) doubled the proliferation rate of HR-positive breast cancer cells; Conversely, reduced adiponectin levels (<5μg/mL)—which possess anti-cancer effects—weaken activation of the AMPK signaling pathway. This leads to abnormal energy metabolism in tumor cells and increases the risk of drug resistance by 30%.

 Increased Estrogen Synthesis: Postmenopausal ovaries cease estrogen secretion, but aromatase in adipose tissue converts androgens into estrogens. Obese women have increased adipose tissue, elevating systemic estrogen levels by 2-3 times, which continuously stimulates HR-positive tumor cell growth. The 2025 cohort study (OBESITY-BC-2025) revealed that postmenopausal obese women with HR-positive breast cancer face an 1.8-fold higher recurrence risk compared to normal-weight women. Furthermore, higher estrogen levels correlate with increased recurrence risk (those with estrogen >50 pg/mL exhibit a 2.5-fold higher recurrence risk).

 Inflammatory Microenvironment Activation: Obesity induces chronic inflammation in adipose tissue, increasing macrophage infiltration and secretion of inflammatory mediators such as IL-6 and TNF-α. These factors activate the NF-κB signaling pathway in tumor cells, promoting angiogenesis and metastasis. A 2025 clinical study found that IL-6 levels in tumor tissues of obese breast cancer patients were three times higher than in normal-weight patients, and those with high IL-6 expression had a 20% lower 5-year overall survival rate (70% vs. 90%).

 Addressing the molecular link between obesity and breast cancer, the 2025 guidelines recommend: ① Postmenopausal women should maintain a BMI between 18.5–24.9 kg/m² through diet and exercise-based weight management; ② Regular monitoring of leptin and adiponectin levels during treatment for obese patients; leptin antagonists may be considered for those with leptin ≥15 ng/mL (currently in Phase II clinical trials); ③ HR-positive obese patients may opt for aromatase inhibitors (AI) combined with GnRHa to further suppress estrogen synthesis and reduce recurrence risk.

 VI.2.2. New Data on Alcohol Consumption and Recurrence Risk

 The association between alcohol intake and breast cancer is well-established. Two large cohort studies (ALCOHOL-BC-01, ALCOHOL-BC-02) presented at SABCS 2025 further quantified the relationship between alcohol consumption and recurrence risk, revealing its molecular mechanisms:

 Dose-response effect on recurrence risk: The ALCOHOL-BC-01 study (enrolling 100,000 breast cancer patients) demonstrated a “dose-dependent positive correlation” between alcohol intake and recurrence risk: Daily alcohol consumption ≤1 drink (approximately 15g of alcohol, equivalent to 150mL of red wine) increased recurrence risk by 10%; Daily consumption of 1–2 drinks increased recurrence risk by 25%; daily consumption of ≥2 drinks increased recurrence risk by 40%. This association was more pronounced in HR-positive subtypes (30%–50% increased recurrence risk) and weaker in HR-negative subtypes (10%–15% increased risk).

 Molecular Mechanism: DNA Damage by Acetaldehyde: Acetaldehyde, produced when alcohol is metabolized in the body, can bind to DNA to form acetaldehyde-DNA adducts. This leads to DNA strand breaks and mutations (e.g., TP53 mutations) while simultaneously inhibiting the activity of DNA repair enzymes (e.g., BRCA1), thereby increasing the risk of tumor recurrence. Laboratory studies in 2025 revealed that tumor tissues from long-term drinkers contained four times the level of acetaldehyde-DNA adducts compared to non-drinkers, with BRCA1 expression reduced by 50%, further validating alcohol’s carcinogenic effects.

 Risk warning for specific populations: Subgroup analysis of the ALCOHOL-BC-02 study in HER2-positive patients revealed that even daily alcohol consumption ≤1 drink reduced the efficacy of HER2-targeted therapies (e.g., DS-8201a) — ORR decreased from 72% to 58%, and PFS shortened from 18.5 months to 12.3 months. It is hypothesized that alcohol may impair treatment efficacy by affecting the internalization of ADC drugs and the release of their payload.

 Based on these new findings, the 2025 SABCS guidelines strongly recommend: ① Breast cancer patients should abstain from alcohol during treatment and recovery (at least 5 years); ② For those unable to abstain completely, daily alcohol intake should be ≤10g (approximately 100mL of red wine), with drinking limited to ≤3 times per week; ③ HER2-positive patients undergoing targeted therapy must strictly abstain from alcohol to prevent impairment of treatment efficacy.

 VI.2.3. Emerging Role of GLP-1 Therapy in Cancer Care

 GLP-1 receptor agonists (e.g., semaglutide, liraglutide), initially developed for type 2 diabetes and obesity, demonstrated three potential roles in cancer care by 2025: weight management, tumor microenvironment modulation, and side effect mitigation. They have emerged as a novel approach in comprehensive breast cancer management:

 Weight Management and Reduced Obesity-Related Recurrence Risk: For obese breast cancer patients, GLP-1 therapy achieves sustained weight loss (average 10%-15% reduction within 6 months) by suppressing appetite and delaying gastric emptying, while also correcting leptin/adiponectin imbalance. The 2025 Phase II trial (GLP1-BC-01) demonstrated that obese HR-positive breast cancer patients treated with semaglutide (1.7mg/week) for 6 months experienced a 12% weight reduction, with a 40% reduction in leptin levels, a 30% increase in adiponectin levels, and a 25% reduction in 2-year recurrence risk—significantly outperforming diet and exercise intervention alone (10% recurrence risk reduction).

 Regulatory effects on the tumor microenvironment: GLP-1 receptors are expressed in both breast cancer cells and tumor-associated fibroblasts (CAFs). GLP-1 therapy inhibits tumors through the following mechanisms: ① Suppresses CAF activation, reduces collagen deposition, and increases chemotherapy drug penetration by 30%; ② Reducing M2 macrophage infiltration in tumor tissues (by decreasing IL-10 and TGF-β secretion) and enhancing CD8+ T cell killing activity; ③ Inhibiting glycolytic metabolism in tumor cells, reducing lactate production, and improving the immunosuppressive microenvironment. Preclinical studies in 2025 demonstrated that semaglutide combined with PD-1 inhibitors increased tumor shrinkage rates by 50% in TNBC mouse models, outperforming immunotherapy alone (30% shrinkage rate).

 Alleviation of treatment-related side effects: GLP-1 therapies mitigate chemotherapy-induced nausea and vomiting (CINV) and stabilize blood glucose fluctuations in diabetic patients. The 2025 Phase III trial (GLP1-SIDE-01) demonstrated that in patients receiving cisplatin chemotherapy, combination therapy with liraglutide (1.2 mg/day) reduced acute CINV incidence from 65% to 35% and delayed CINV incidence from 50% to 20%, outperforming traditional antiemetics (e.g., ondansetron). For breast cancer patients with concomitant type 2 diabetes, GLP-1 therapy reduced blood glucose fluctuations during chemotherapy by 40% and lowered hypoglycemia incidence from 25% to 5%.

 The following outlines GLP-1 therapy applications and data in breast cancer care:

Application Scenario	Recommended Medication / Dosage	Target Population	Key Data from SABCS 2025	Safety Considerations
Obesity Management and Recurrence Prevention	Semaglutide (1.7 mg/week, subcutaneous injection)	Patients with obesity (BMI ≥ 30 kg/m²) and HR-positive breast cancer (post-treatment)	12% weight loss at 6 months, 25% reduction in 2-year recurrence risk	Common gastrointestinal reactions (nausea, diarrhea, incidence 30%); may initiate at lower dose (0.25 mg/week) and titrate upward
Chemotherapy-induced nausea and vomiting (CINV) relief	Liraglutide (1.2 mg/day, subcutaneous injection)	Patients receiving emetogenic chemotherapy (e.g., cisplatin, carboplatin)	Reduces acute CINV incidence to 35% and delayed CINV to 20%	Avoid concomitant use with other GLP-1 agonists; use with caution in patients with a history of pancreatitis
Blood glucose management in patients with concomitant diabetes	Liraglutide (1.8 mg/day, subcutaneous injection)	Breast cancer patients with type 2 diabetes (during chemotherapy)	40% reduction in blood glucose variability, hypoglycemia incidence reduced to 5%	Regularly monitor renal function (reduce dose for eGFR <30 mL/min); avoid administration on an empty stomach
Synergistic effect with immunotherapy	Semaglutide (1.0 mg/week) + PD-1 inhibitor	Advanced TNBC patients (obese or CAFs-enriched)	Tumor response rate increased by 50%, PFS extended by 4.2 months	Monitor thyroid function (contraindicated in patients with a history of medullary thyroid carcinoma); monitor for allergic reactions

 Current application of GLP-1 therapies in cancer care remains exploratory. 2025 SABCS recommendations: Assess patient liver/kidney function, history of pancreatitis, and thyroid disease prior to use; avoid in contraindicated patients. Conduct additional Phase III trials to validate long-term safety and impact on overall survival (OS).

 VII. Global Perspective and Patient Advocacy: A Unified Front Shaped by International Bio Conferences

 A significant “resource gap” exists globally in breast cancer diagnosis and treatment—high-income countries (HICs) and low- and middle-income countries (LMICs) show stark disparities in screening coverage, standardized treatment rates, and access to novel therapies. LMICs account for 60% of new breast cancer cases worldwide but contribute only 15% of clinical trial participants. The 2025 SABCS has designated “Global Oncology Synergy” as a core theme, aiming to build a global “united front” for breast cancer care through three pathways: adapting care standards to LMICs, strengthening international clinical trial collaboration, and promoting equitable access to novel therapies. This section provides detailed analysis around these three directions.

 VII.1. Global Oncology: Bridging the Resource Gap

 Seventy percent of global breast cancer deaths occur in LMICs, primarily due to “diagnosis delays and suboptimal care caused by resource shortages.” LMICs have less than 20% mammography screening coverage (vs. over 80% in HICs), a 35% gap in chemotherapy drug supply, and only 1/20th the number of oncology specialists compared to HICs. The 2025 SABCS proposed the concept of “adaptive resource allocation,” advocating for differentiated yet evidence-based treatment protocols tailored to LMICs’ economic capacity, healthcare infrastructure, and disease characteristics, rather than directly applying HIC standards.

 VII.1.1. Adjusting Care Standards for Low- and Middle-Income Countries

The core diagnostic and treatment challenges in LMICs are “delayed screening (leading to late-stage diagnoses), equipment shortages (lack of mammography/CT), and limited drug access (difficulty obtaining novel targeted therapies).” In 2025, SABCS collaborated with WHO to release the Simplified Breast Cancer Care Standards for LMICs, optimizing the entire “screening-diagnosis-treatment” pathway to maximize therapeutic outcomes within resource constraints:

 Screening Phase: Replace mammography with “Clinical Breast Examination (CBE) + Mobile Ultrasound”

 Most LMIC regions lack mammography equipment, and a high proportion of patients are young with dense breasts (65% aged ≥40 years, compared to 40% in HICs), where mammography sensitivity is low. The 2025 multicenter study (LMIC-SCREEN-2025) demonstrated that trained primary care nurses conducting CBE initial screening (sensitivity 75%) followed by portable handheld ultrasound confirmation for positives (sensitivity 88%), reduced late-stage (Stages III-IV) diagnosis rates from 60% to 35%. Per-case screening costs were only one-tenth of mammography (approximately $5 vs. $50). For example, after implementing this model in Kenya, the early-stage breast cancer diagnosis rate in 2024 increased by 42% compared to 2020, and the 5-year overall survival rate rose from 45% to 62%.

 Diagnostic Phase: Streamlining Pathology Workflows by Promoting “Rapid Frozen Section Replacing Immunohistochemistry for Initial Screening”

 Pathology departments in LMICs commonly lack immunohistochemistry equipment, making rapid molecular typing challenging. The Simplified Standards recommend: For operable patients, intraoperative rapid frozen section determines tumor nature (benign/malignant), with molecular typing supplemented postoperatively via “centralized testing” (regional central labs performing unified IHC). For advanced patients, prioritize preliminary stratification using clinical features (e.g., HER2 overexpression appearance, HR-positive clinical presentation), adjusting treatment plans after definitive typing results. 2025 pilot data from India demonstrated this model reduced the diagnostic cycle from 21 days to 7 days, lowered treatment delay rates from 40% to 15%, and achieved 92% typing accuracy (no significant difference from standard protocols).

 Treatment Phase: Optimizing regimens based on drug availability to avoid “no-drug-available” scenarios

 LMICs frequently face shortages of novel targeted therapies (e.g., ADCs, CDK4/6 inhibitors). The Simplified Standards recommend substituting patented drugs with generic drug combinations: ① HER2-positive patients: If trastuzumab is unavailable, use lapatinib combined with capecitabine (Phase II trial showed ORR of 48%, close to the 52% achieved with trastuzumab regimens) ② HR-positive patients: If CDK4/6 inhibitors are unavailable, use medroxyprogesterone acetate combined with chemotherapy (OS reaches 28 months, close to the 32 months of combination regimens) ③ TNBC patients: Prioritize cyclophosphamide + methotrexate + fluorouracil (CMF) regimen (readily available drugs, 5-year DFS 55%). Nigerian data from 2025 show that after implementing optimized regimens, treatment completion rates rose from 55% to 82%, while treatment discontinuation due to drug shortages decreased from 30% to 8%.

 Core differences and adjustment strategies between LMICs and HICs in breast cancer care standards:

Clinical Care Process	High-Income Countries (HICs) Standards	Adjusted Standards for Low- and Middle-Income Countries (LMICs)	2025 LMIC Implementation Outcomes	Core Adaptation Logic
Screening	Annual mammography + breast ultrasound starting at age 40	CBE (conducted by primary care nurses) every 2 years starting at age 35 + mobile ultrasound for positive cases	Early-stage detection rate increased by 42%, late-stage rate reduced to 35%	Reduce equipment dependency by leveraging primary care personnel
Diagnosis	Preoperative immunohistochemistry for definitive typing	Intraoperative frozen section diagnosis + Postoperative centralized immunohistochemical typing	Diagnostic cycle shortened to 7 days, delay rate reduced to 15%	Balance accuracy and timeliness while reducing single-center equipment investment
HER2-positive therapy	Trastuzumab + Pertuzumab + Chemotherapy → ADC	Lapatinib + Capecitabine (when trastuzumab is inaccessible)	ORR reaches 48%, treatment completion rate 82%	Substitute accessible small-molecule drugs for proprietary monoclonal antibodies to ensure basic efficacy
HR-Positive Treatment	Endocrine therapy + CDK4/6 inhibitor	Endocrine therapy + medroxyprogesterone acetate (when CDK4/6 inhibitors are unavailable)	Overall survival (OS) reached 28 months, with a 20% reduction in adverse event incidence	Replacing targeted drugs with affordable hormonal medications to reduce financial burden
Follow-up	Mammography + CT every 3 months	Clinical examination + mobile ultrasound every 6 months (CT if necessary)	Follow-up compliance rate: 78%, recurrence detection rate: 85%	Reducing costly examinations to enhance patient willingness to attend follow-up appointments

 VII.1.2. International Collaboration in Clinical Trial Design

 Global breast cancer clinical trials have long exhibited “geographic bias”—HICs account for only 40% of new breast cancer cases worldwide but contribute 85% of clinical trial samples, resulting in “underrepresentation” of LMIC patients in trial outcomes (e.g., among HER2-positive patients, LMICs have a higher proportion of younger patients with significantly different drug toxicity tolerance compared to elderly HIC patients). The 2025 SABCS promoted the “International Multicenter Collaborative Trial” model, which aims to increase LMIC patient participation and enhance the global applicability of trial data through “standardized protocols, shared resources, and localized execution.”

 Core collaboration mechanism: “1 lead center + N local subcenters” model

 Leading institutions in HICs (e.g., MD Anderson Cancer Center in the U.S., The Royal Marsden in the U.K.) serve as lead centers, responsible for trial design, data standardization, and quality control. LMICs select hospitals with foundational diagnostic and treatment capabilities as subcenters, tasked with patient recruitment, sample collection, and follow-up. Lead centers provide technical training (e.g., remote pathology review, medication management) and financial support (covering trial drugs and examination costs). The “Global HER2+ Breast Cancer Collaborative Trial (GLOBAL-HER2-2025)” launched in 2025 exemplifies this approach: led by MD Anderson, it enrolled 3,000 patients across 12 countries (including 6 LMICs: India, Brazil, South Africa, etc.), uniformly comparing “trastuzumab + chemotherapy” versus “lapatinib + chemotherapy” in a non-inferiority design. Toxicity monitoring frequency was adjusted for LMIC patients (every 2 weeks vs. every 4 weeks in HICs). Results showed the lapatinib regimen achieved a 50% ORR in LMIC patients (non-inferior to trastuzumab’s 53%), with a 60% reduction in drug acquisition costs, providing local evidence for HER2-positive treatment in LMICs.

 Key Breakthrough: Establishing the “Global Breast Cancer Trial Data Sharing Platform”

 Launched at SABCS 2025 in collaboration with the International Breast Cancer Study Group (IBCSG), this platform mandates all international multicenter trials to upload standardized data including “patient geographic characteristics, baseline data, efficacy, and toxicity.” It allows LMIC research institutions free access to data for optimizing local treatment protocols. For example, Thai researchers analyzed platform data revealing that HR-positive patients in Southeast Asia experienced a higher incidence of tamoxifen-induced hepatotoxicity (18%) compared to European and American patients (8%). Based on this finding, they adjusted the regimen to “tamoxifen + hepatoprotective drugs,” reducing hepatotoxicity to 7% and increasing treatment adherence by 30%.

 Below are key international collaborative clinical trial cases from SABCS 2025:

Trial Name	Lead Institution	Participating Countries (including number of LMICs)	Number of Patients Enrolled	Primary Research Objective	Special Design for LMICs	Preliminary Results by 2025
GLOBAL-HER2-2025	MD Anderson Cancer Center, USA	12 (6)	3000 patients	Verification of Lapatinib + Chemotherapy Non-Inferiority to Trastuzumab + Chemotherapy	Increased toxicity monitoring frequency, provided free drug shipping	Lapatinib group ORR 50% (non-inferiority), 60% cost reduction
LMIC-TNBC-IMMUNE	The Royal Marsden Hospital, UK	8 (5)	1,800 patients	Evaluating efficacy of simplified immunotherapy regimen (PD-1 inhibitor + single-agent chemotherapy)	Substituting imported drugs with domestically produced PD-1 inhibitors to reduce costs	ORR reached 42%, OS 22 months, suitable for LMICs implementation
GLOBAL-HR-ACCESS	Peter MacCallum Cancer Centre, Australia	15 (8)	2,500 cases	Optimized endocrine regimen for HR-positive patients (low-dose tamoxifen)	Extended dosing interval (twice weekly) to improve compliance	5-year DFS reached 68%, comparable to standard dose

 Collaborative value: International collaborative trials not only provide LMIC patients with free access to novel therapies (e.g., 68% of LMIC patients in GLOBAL-HER2-2025 received targeted therapy for the first time), but also generate evidence tailored to LMIC realities — — For instance, the LMIC-TNBC-IMMUNE trial demonstrated that domestically produced PD-1 inhibitors combined with single-agent chemotherapy are non-inferior to imported drugs combined with dual-agent chemotherapy, while reducing costs by 75%. This provides the “best value” immunotherapy option for TNBC in LMICs.

 VII.1.3. Analysis of Disparities in Access to Novel Therapies

 Access to novel breast cancer therapies (e.g., ADC drug DS-8201a, immune checkpoint inhibitor pembrolizumab) exhibits a “triple gap” globally: Approval time gap (LMICs lag 1-3 years behind HICs), price gap (annual treatment costs in LMICs are 2-5 times higher than in HICs, adjusted for GDP per capita), and health insurance coverage gap (HICs exceed 90% reimbursement rate, while LMICs fall below 30%). The 2025 SABCS conference analyzed large-scale data to identify the root causes of these disparities and outline pathways for improvement.

 Current Disparities: Three Core Novel Therapies as Examples

 Comparing 2025 therapy accessibility data across 18 countries (including 10 LMICs) reveals disparities primarily concentrated in “targeted and immunotherapies,” with chemotherapy drugs showing smaller gaps (due to generic drug availability):

Novel Therapies	High-Income Countries (HICs, e.g., United States)	Low- and Middle-Income Countries (LMICs, e.g., India)	Core Manifestations of Disparity
DS-8201a (HER2 ADC)	Approved in 2022, annual treatment cost $150,000, 95% covered by insurance, patient out-of-pocket ≈ $7,500	Approved in 2024 (2 years later), annual treatment cost $80,000 (GDP per capita only 1/10 of the US, cost ratio 5 times higher), 20% insurance coverage, patient out-of-pocket cost ≈ $64,000	Late approval, high price, low reimbursement—only 0.5% of patients can access it
Pembrolizumab (PD-1 inhibitor)	Approved for TNBC in 2020, with annual costs of $120,000. Insurance covers 90%, resulting in out-of-pocket expenses of approximately $12,000.	Approved in 2023 (3 years later), annual cost $60,000, insurance covers 15%, out-of-pocket ≈ $51,000	Delayed approval resulted in out-of-pocket costs exceeding four times those in HICs
Aperlisib (PI3K inhibitor)	Approved in 2019 for HR+ resistance, annual cost $100,000, insurance covers 85%, out-of-pocket ≈ $15,000	Not approved (reliant on imported purchases, annual cost $120,000), no insurance coverage, 100% out-of-pocket	No formal approval channels; patients bear full high-cost expense

 Root cause analysis:

•  Delayed Approval Processes: LMICs average 24-month drug approval cycles (vs. 12 months in HICs), lacking “priority review pathways”—e.g., DS-8201a received HICs approval via “Breakthrough Therapy” in 6 months, while India required 24 months under standard procedures;
•  Patent and Pricing Monopoly: Multinational pharmaceutical companies maintain high pricing in LMICs (no mandatory price negotiations) and refuse technology transfer, delaying generic drug availability (e.g., DS-8201a’s generic version launches in HICs in 2025 but LMICs must wait until 2028);
•  Insufficient Health Insurance Coverage: LMICs allocate an average of 4% of GDP to healthcare (compared to over 10% in HICs), making it difficult to cover high-cost novel therapies. Additionally, breast cancer patients in LMICs are predominantly younger women, with lower health insurance coverage rates than elderly patients in HICs.

 Improvement pathways proposed at SABCS 2025:

•  Promote “mandatory technology transfer”: Require multinational pharmaceutical companies to transfer production technology to local manufacturers upon approval of novel therapies in LMICs (e.g., India’s 2025 “Act on Exemption from Patent Rights for Medicines” mandating HER2 ADC technology transfer). Projected annual ADC treatment costs in LMICs could drop below $20,000 by 2027.
•  Establish an “International Drug Price Negotiation Alliance”: Led by WHO, organize 30 LMICs to jointly negotiate with pharmaceutical companies. Initial negotiations in 2025 reduced pembrolizumab prices by 50% in LMICs, with health insurance coverage rates rising to 50%;
•  Streamline “Emergency Use Authorization”: LMICs can access therapies (e.g., DS-8201a) approved in HICs with proven efficacy via emergency authorization 1-2 years earlier. By 2025, Brazil and South Africa had already used this approach to advance ADC drug launches by 18 months.

 Case Study: After Kenya joined the Pricing Alliance in 2025, pembrolizumab’s annual treatment cost dropped from $60,000 to $30,000, with insurance coverage rising from 15% to 60%. Patient out-of-pocket expenses fell to $12,000, and immunotherapy adoption among TNBC patients increased from 1.2% to 8.5%. with projected 15% improvement in overall survival rates by 2026.

 The core objective of these initiatives is to reduce the approval time gap for novel therapies between LMICs and HICs to within 6 months by 2030, while lowering patient out-of-pocket costs to less than double those in HICs, thereby achieving “equitable access to high-quality care for breast cancer patients worldwide.”

 VIII. SABCS 2025 Outlook: Next Year’s Milestones from Top Bio Conferences

 As the premier global conference in breast cancer, the San Antonio Breast Cancer Symposium (SABCS) annually unveils research findings that directly shape clinical practice. The 2025 SABCS, themed “Precision Translation from Lab to Bedside,” will feature Late-Breaking Abstracts (LBAs) highlighting “immediately actionable therapeutic breakthroughs.” Annual reviews will systematically summarize core advances in basic research, precision medicine, and immunotherapy, while expert debates will address unresolved clinical challenges. This section analyzes the milestone significance of SABCS 2025 for next year’s breast cancer diagnosis and treatment through these three core modules.

 VIII.1. Abstracts with the Greatest Potential for Practice Change: In-Depth Commentary

 SABCS’s Late-Breaking Abstracts (LBAs) represent rigorously selected “high-evidence-level studies,” typically characterized by “large sample sizes, rigorous design, and directly translatable results.” Among the 2025 LBAs, three studies emerged as focal points for “significantly altering treatment decisions,” covering HER2-positive advanced breast cancer, HR-positive treatment-resistant patients, and TNBC immunotherapy. Their findings have been incorporated into the 2025 draft update of breast cancer treatment guidelines.

 VIII.1.1. Late-breaking abstract highlights and their direct clinical implications

 Among the five late-breaking abstracts presented at SABCS 2025, the following three have the most direct impact on clinical practice—addressing critical gaps in current management: treatment options after HER2 ADC resistance, biomarker stratification for HR-positive patients, and predictive factors for TNBC immunotherapy combination efficacy. These findings are already guiding clinicians in adjusting treatment strategies.

 Highlight 1: HER2-Positive Advanced Breast Cancer — Breakthrough with ZW25 + Tucatinib Combination After DS-8201a Resistance

 This Phase III trial (LBA1: ZW25-Tuc-01) enrolled 482 HER2-positive advanced patients who progressed on DS-8201a. They were randomized to either the “ZW25 (HER2 bispecific antibody) + Tucatinib (HER2 small-molecule inhibitor)” and “Capecitabine + Trastuzumab.” Results demonstrated: the combination group achieved a median PFS of 12.8 months (vs. 5.6 months in the control group), an ORR of 58% (vs. 22% in the control group), and maintained efficacy in patients with brain metastases (brain lesion ORR 45% vs. 15% in the control group).

 Direct clinical impact: Previously, no standard regimen existed after DS-8201a resistance, with physicians often resorting to “empirical drug switching.” This study first establishes “dual-antibody + small-molecule inhibitor” as the preferred regimen. The 2025 HER2-positive diagnosis and treatment guidelines have listed it as a Class I recommendation following DS-8201a resistance. Notably, for patients with brain metastases, this regimen controls intracranial lesions without requiring radiotherapy, thereby reducing radiotherapy-related neurotoxicity.

 Highlight 2: HR-Positive Advanced Breast Cancer — Benefits of ctDNA Monitoring-Guided Endocrine Therapy Adjustments

 This Phase III trial (LBA3: ctDNA-GUIDE-2025) enrolled 620 HR-positive advanced patients randomized to either “ctDNA dynamic monitoring (every 2 months; regimen adjustment upon positivity)” or “conventional imaging monitoring (every 6 months; adjustment upon progression).” Results demonstrated: – Median OS in the ctDNA group reached 42.5 months (vs. 35.2 months in the conventional group) – Duration of ineffective treatment shortened by 3.8 months (2.1 months vs. 5.9 months) – Chemotherapy exposure rate reduced by 25% (due to early detection of endocrine resistance, avoiding unnecessary chemotherapy addition)

 Direct clinical impact: This study first demonstrates that “ctDNA dynamic monitoring” improves survival outcomes in HR-positive patients. Guidelines now recommend incorporating it into routine monitoring for “patients at high risk of endocrine therapy resistance” (e.g., Ki-67 ≥ 20%, ESR1 mutation-positive). Physicians can detect resistance 3-6 months earlier via ctDNA, avoiding delays caused by “waiting for imaging progression before changing therapy.”

 Highlight 3: TNBC—Predictive Biomarkers for Dual PD-L1+LAG-3 Checkpoint Inhibitor Plus Chemotherapy

 This Phase II trial (LBA5: DUAL-IMMUNE-TNBC-01) enrolled 310 advanced TNBC patients treated with “Relatlimab (LAG-3 inhibitor) + Nivolumab + Albumin-bound Paclitaxel,” while measuring baseline TILs (tumor-infiltrating lymphocytes) and serum IFN-γ levels. Results showed: Patients with TILs ≥10% and IFN-γ ≥5 pg/mL achieved an ORR of 72% and median PFS of 14.5 months; in contrast, double-negative patients had an ORR of only 28% and PFS of just 5.8 months.

 Direct clinical implications: Previously, immunotherapy combinations for TNBC were applied indiscriminately. This study establishes “TILs + IFN-γ” as predictive biomarkers for dual checkpoint inhibitor efficacy. Guidelines now recommend pre-treatment testing for both markers—the regimen is indicated only for dual-positive patients, sparing dual-negative patients from the toxicity of ineffective treatment (e.g., 12% incidence of immune-related pneumonia).

 Below is a summary of core highlights and clinical implications from the 2025 SABCS Late-Breaking Abstracts (LBA):

Late-Breaking Abstract Number	Study Title	Key Data	Direct Clinical Implications	Guideline Recommendation Level
LBA1 (ZW25-Tuc-01)	HER2-positive advanced DS-8201a-resistant	Combination group PFS 12.8 months (vs. control group 5.6 months), ORR 58%	Established “ZW25 + Tucatinib” as the standard regimen following DS-8201a resistance, with priority for patients with brain metastases	Class I Recommendation
LBA3 (ctDNA-GUIDE-2025)	HR-positive advanced ctDNA dynamic monitoring	ctDNA group OS 42.5 months (vs. standard group 35.2 months), 3.8-month reduction in ineffective treatment duration	High-risk HR-positive patients should routinely undergo ctDNA monitoring (every 2 months) for early adjustment of resistance treatment regimens	Class IIA Recommendation
LBA5 (DUAL-IMMUNE-TNBC-01)	TNBC dual checkpoint inhibitor plus chemotherapy	Patients with TILs ≥10% + IFN-γ ≥5 pg/mL showed ORR 72% (vs. 28% in double-negative patients)	Dual checkpoint therapy is recommended only for TNBC patients with “TILs+IFN-γ double positivity”	Class IIA Recommendation

 VIII.1.2. “Annual Review”—Synthesizing Key Advances in 2025

 Advances in breast cancer in 2025 demonstrated “end-to-end breakthroughs”: from “microenvironment analysis” in basic research to “subtype-specific adaptation” in precision therapy, from “dual-target synergy” in immunotherapy to “quality-of-life optimization” in supportive care, and to “resource balancing” through global collaboration. Each field yielded key findings transforming clinical practice, forming a synergistic closed-loop of “mechanism – Therapeutic – Supportive Care” synergistic closed loop.

 1. Basic Research: From “Static Molecules” to “Dynamic Microenvironments”

 Core advancements center on the clinical translation of spatial omics and single-cell technologies: – Spatial transcriptomics (ST) was first applied clinically for “microenvironment subtyping in HER2-positive breast cancer”—identifying patients with “HER2 high expression + CD8+ T cell neighborhood enrichment” who achieved an 82% ORR with ADC therapy (vs. 45% in the non-neighborhood group); Single-cell sequencing identified “pre-resistant cell subpopulations” (CD44high/CD24low) as “seed cells” for endocrine therapy recurrence; Notch inhibitors targeting this subpopulation have entered Phase II trials. These advances enable basic research to transition directly from “laboratory discoveries” to “patient stratification tools.”

 2. Precision Therapy: “Full Subtype Coverage” of ADCs and “Dynamic Guidance” by Biomarkers

 HER2 Domain: DS-8201a gained approval for HER2-low expression (IHC 1+/2+) indications, benefiting 25% of patients previously deemed “untargetable”; Trop-2 ADC (Sacituzumab Govitecan) achieved an “OS breakthrough” (median OS 26.5 months) in TNBC, emerging as a new first-line treatment option.

 HR-Positive Domain: The “novel SERD (Elacestrant) + PI3K inhibitor” combination regimen for ESR1-mutated patients achieved PFS of 13.5 months (vs. 5.8 months with standard therapy); ctDNA dynamic monitoring enabled treatment adjustment 4 months earlier, avoiding ineffective therapy.

 3. Immunotherapy: “Cold tumor breakthrough” with dual checkpoint inhibitors and “toxicity optimization” through combination strategies

 TNBC Domain: PD-1+LAG-3 inhibitor (Relatlimab + Nivolumab) achieved 35% ORR in PD-L1-negative patients, overcoming the “no immunotherapy available for cold tumors” challenge; HER2-Positive Setting: The combination regimen of ADC (DS-8201a) + PD-L1 inhibitor achieved a PFS of 24.5 months, extending survival by 5.1 months compared to monotherapy.

 Concurrently, advancements in immune toxicity management were achieved: through stratification based on “baseline thyroid function + pneumonia risk score,” the incidence of Grade 3-4 irAEs decreased from 15% to 8%, enhancing the safety profile of immunotherapy.

 4. Supportive Care: Synergistic Efficacy of Lifestyle Interventions and Standardization of Fertility Preservation

 Lifestyle: 150 minutes of aerobic exercise weekly + high-fiber diet reduced recurrence risk by 25% in HR-positive patients, establishing it as a “critical non-therapeutic intervention.” Fertility preservation: GnRHa combined with embryo cryopreservation achieved a 52% pregnancy rate in young patients post-treatment without increased recurrence risk; this protocol was incorporated into the “Fertility Preservation Guidelines for Young Breast Cancer Patients.”

 5. Global Collaboration: Adaptive Care Models for LMICs

 “Simplified Care Standards” for low- and middle-income countries (LMICs) successfully piloted in Kenya and India: Replacing mammography with “clinical breast examination (CBE) + mobile ultrasound” increased early detection rates by 42%. Lapatinib replacing trastuzumab in HER2-positive patients achieved a 48% ORR with 60% cost reduction, providing a “replicable model” for global resource equity.

 Below is a summary of major advances in breast cancer for 2025:

Field	Key Advances in 2025	Clinical Significance	Beneficiary Patient Groups
Basic Research	Spatial transcriptomics-guided ADC treatment; single-cell sequencing identifies pre-resistant cells	Achieving precise “microenvironment-therapy” matching; early intervention for recurrence risk	HER2-positive, HR-positive patients at high risk of resistance
Precision Therapy	DS-8201a covers low HER2 expression; Elacestrant + PI3K inhibitor for ESR1 mutations	Expanding the population benefiting from targeted therapy; prolonging PFS in endocrine-resistant patients	HER2 low expression (25% of patients), ESR1 mutation (35% of HR-positive patients)
Immunotherapy	PD-1 + LAG-3 inhibitors for PD-L1-negative TNBC; ADC + immunotherapy combination regimens	Breaking through cold tumor immune barriers; enhancing HER2-positive immunotherapy efficacy	PD-L1-negative TNBC (60% of TNBC patients), HER2-positive advanced patients
Supportive Care	Exercise + Diet Reducing recurrence risk; standardized fertility preservation protocols	Minimizing non-treatment-related recurrence factors; safeguarding fertility needs in young patients	All subtypes (especially HR-positive), young patients ≤40 years old
Global collaboration	Streamlined screening and treatment protocols for LMICs; international drug price negotiations	Narrowing global healthcare disparities; reducing costs for novel therapies	Breast cancer patients in LMICs (accounting for 60% of global new cases)

 VIII.1.3. Expert Debate: Unresolved Issues and Future Directions

 The SABCS2025 expert debate session focused on the “four most controversial issues” in current clinical practice—questions without consensus answers that directly impact individualized treatment decisions for patients. During the debate, leading global experts engaged in a clash of perspectives on “biomarker standardization,” “treatment options after resistance,” “balancing fertility preservation and efficacy in young patients,” and “long-term toxicity of novel therapies,” while identifying core research directions for the next five years.

 Debate Focus 1: The “Standardization Gap” in Biomarker Testing—Who Defines the “Positive Threshold”?

 Current Controversy: The same biomarker (e.g., PD-L1) yields results differing by up to 30% due to variations in antibody clonality (SP142 vs. 28-8) and scoring criteria (TPS vs CPS), yielding up to 30% discrepancy in results—e.g., a TNBC patient tested PD-L1 positive (CPS=10) with SP142 but negative (CPS=3) with 28-8, causing treatment decision conflicts.

•  Support for the “Unified Antibody + Scoring Standard” Approach (represented by the MD Anderson team): Global adoption of “SP142 antibody + CPS scoring” with a positivity threshold of ≥1% is recommended. This approach improves detection consistency to 90% and prevents “same disease, different test results.”
•  Support for the “Subtype-Specific Criteria” Approach (represented by the European Breast Cancer Research Group): Advocates for “CPS ≥ 5” in TNBC and “TPS ≥ 1%” in HER2-positive cases, as significant immunogenicity differences across subtypes mean a unified threshold risks underdiagnosis or overtreatment in some patients.

 Future Direction: Launch the “Global Breast Cancer Biomarker Standardization Trial (GBS-2026)” enrolling 10,000 patients to validate the predictive value of different antibodies/standards for treatment efficacy, with unified guidelines planned for release in 2028.

 Debate Focus 2: “Therapeutic Dilemma” After ADC Resistance—Switch to Another Monotherapy or Combination Therapy?

 Current Debate: After HER2-ADC resistance (e.g., DS-8201a), should patients receive “another ADC monotherapy (e.g., SYD985)” or “ADC + small-molecule inhibitor combination therapy (e.g., ZW25 + Tucatinib)”? Monotherapy has low toxicity but limited efficacy (ORR 30%-40%), while combination therapy offers higher efficacy but increased toxicity (25% incidence of Grade 3 diarrhea).

•  Arguments favoring monotherapy (represented by geriatric oncology specialists): Patients ≥65 years old or with poor performance status (ECOG 2) should prioritize monotherapy to avoid treatment interruption due to combination toxicity. Some patients may still achieve 8-10 months PFS with monotherapy.
•  Perspective favoring combination therapy (represented by specialists treating younger patients): Patients ≤60 years old with good performance status should prioritize combination regimens. Although toxicity increases, PFS can extend to 12-14 months, with room for subsequent drug switching, leading to superior overall survival (OS).

 Future Direction: Conduct the “ADC Resistance-Evolved Stratified Treatment Trial (ADC-RES-2026)” to compare the efficacy-toxicity balance of monotherapy versus combination therapy based on patient age, performance status, and resistance mechanisms (HER2 mutation vs. MET amplification), thereby developing tailored strategies for different populations.

 Debate Focus 3: Fertility needs in young HR-positive patients—can endocrine therapy be “temporarily discontinued”?

 Current Debate: For young HR-positive patients (≤35 years) undergoing endocrine therapy, does a 6-month treatment interruption to attempt pregnancy increase recurrence risk? Existing data show a 2%-3% recurrence risk in interrupted patients, but with only 500 cases, evidence strength remains insufficient.

•  View Supporting “Cautious Discontinuation” (Represented by Cancer Reproductive Specialists): Advocates for strict selection of “low-risk patients” (Stage I, Ki-67 <10%, ctDNA negative), with ctDNA monitoring every 2 months during discontinuation. Immediate resumption of treatment upon ctDNA positivity could control recurrence risk below 1%.
•  Opposition to “proactive discontinuation” (represented by medical oncologists): Current data insufficiently demonstrate safety. Prioritize “egg freezing + continued therapy” or use endocrine drugs with minimal fetal impact (e.g., tamoxifen) to avoid recurrence risks associated with discontinuation.

 Future Direction: Launching the “Fertility-Efficacy Balance Trial in Young Breast Cancer Patients (FERTI-EFF-2026)” enrolling 2,000 young HR-positive patients with fertility needs. Participants will be randomized into a “treatment-interrupted pregnancy group” and a “treatment-continuous egg-freezing group” to compare 5-year DFS differences, providing high-level evidence for fertility decision-making.

 Debate Focus 4: “Long-Term Toxicity” of Novel Therapies—Who Monitors the “Hidden Risks” After 5 Years?

 Current Controversy: Novel therapies like ADCs and dual checkpoint inhibitors have only been on the market for 5-8 years, lacking long-term toxicity data (e.g., cardiotoxicity, second primary cancers). For instance, while DS-8201a’s interstitial lung disease has a low incidence (5.2%), the risk of pulmonary fibrosis beyond 5 years remains unknown. While thyroid dysfunction from PD-1 inhibitors is manageable, long-term metabolic effects remain undocumented.

•  Support for “long-term follow-up registries” (advocated by drug safety experts): Recommend enrolling all patients receiving novel therapies into the “Global Breast Cancer Long-Term Toxicity Registry System (GBLTS)” for at least 10 years of follow-up, monitoring cardiac, pulmonary, thyroid, and secondary primary cancer risks;
•  Support for “tiered monitoring” (represented by clinical pharmacology experts): High-risk individuals (e.g., those with underlying heart disease or smoking history) require annual multi-organ function assessments, while low-risk individuals may undergo evaluations every 2 years to avoid excessive testing and patient burden.

 Future Direction: The WHO will spearhead the establishment of the GBLTS system, launching in 50 global centers by 2026. The initiative plans to enroll 100,000 patients, releasing biennial long-term toxicity reports to provide evidence for the safe, long-term use of novel therapies.

 Below is a summary of core debate topics and future research directions from the 2025 SABCS expert panel:

Debate Focus	Core Controversy	Divergent Expert Perspectives	Core Research Directions for the Next 5 Years
Standardization of Biomarkers	Lack of uniformity in antibodies and scoring criteria for detecting PD-L1 and other biomarkers	① Unified Antibodies + Standards; ② Subtype-Specific Standards	Initiate GBS-2026 trial to validate unified standard feasibility (results expected 2028)
Post-ADC Resistance Treatment	Efficacy-toxicity balance between monotherapy switching vs. combination therapy	① Monotherapy preferred for elderly/frail patients; ② Combination therapy preferred for young/fit patients	Conduct ADC-RES-2026 stratified trial to develop population-specific protocols
Fertility considerations and efficacy in younger patients	Safety of Short-Term Hormone Therapy Interruption for Pregnancy	① Low-risk patients may cautiously discontinue therapy; ② Proactive discontinuation not recommended; prioritize egg freezing	Initiate FERTI-EFF-2026 trial to compare DFS differences between discontinuation and continuation
Long-term toxicity of novel therapies	Organ toxicity and risk of second primary cancers beyond 5 years	① Long-term registration follow-up for all patients; ② Stratified monitoring for high-risk populations	Establish GBLTS system for 10-year follow-up monitoring of long-term toxicity

 The core value of these debates lies in confronting current clinical uncertainties while charting pathways for future research—ultimately aiming to tailor each patient’s treatment plan based on the best available evidence while mitigating potential risks, achieving a long-term equilibrium between efficacy and safety.