Editor's Note: Breast cancer is the most commonly diagnosed malignancy among women worldwide. Looking back over the past century, its diagnosis and treatment have evolved from viewing breast cancer primarily as a locoregional disease treated mainly with surgery, to recognizing its systemic nature and developing systemic therapies, and ultimately to the clinical adoption of molecular subtype-based treatment. Each transformation has brought significant improvements in patient survival and prognosis. Today, with continued advances in genetic testing technologies, breast cancer treatment is evolving further from molecular subtype-based approaches toward precision treatment guided by genetic alterations. Recently, the Northern Breast Cancer Salon was successfully held in Qingdao. Professor Yongmei Yin of Jiangsu Provincial People's Hospital delivered a presentation entitled “Seeing the Subtle to Foresee the Far — The Evolution of Precision Diagnosis and Treatment in Breast Cancer from Molecular Subtyping to Gene-Guided Therapy,” systematically reviewing the evolution and breakthroughs in breast cancer treatment strategies and providing an in-depth interpretation of the emerging landscape of precision therapy, from molecular subtyping to gene-driven treatment. This article summarizes the key points of her presentation, with the aim of providing reference and inspiration for clinical practice.Treating According to Molecular Subtype
Classic Treatment Strategies Based on Breast Cancer “Molecular Subtyping”
In 2000, Perou et al. used cDNA microarray technology involving 8,102 human genes to conduct the first comprehensive analysis of gene expression profiles in breast cancer tissues. The study found that the gene expression patterns of these tumors could form distinctive “molecular portraits” and be classified into intrinsic molecular subtypes characterized by different gene-expression profiles. This landmark discovery marked the formal emergence of the concept of “molecular subtyping” in breast cancer. In 2009, based on this work, the Parker team developed the PAM50 molecular classification by analyzing the expression of 50 genes in breast tumor tissue and classifying breast cancers according to their expression patterns.
Since 2011, immunohistochemical (IHC) results for ER/PR, HER2, and Ki-67 have generally been used in clinical practice as surrogate markers for molecular subtyping. The four key biomarkers each have their own historical milestones. In 1967, Jensen et al. first identified ER and PR receptors in breast cancer cells. In 1977, tamoxifen was approved, ushering in the era of endocrine therapy. In 1983, Gerdes et al. identified the Ki-67 monoclonal antibody, and in 1993, researchers successfully cloned the gene encoding the Ki-67 protein, after which Ki-67 became a gold-standard marker of cellular proliferation. In 1984, Robert Weinberg discovered the HER2/neu gene, while approval of trastuzumab in 1998 ushered in the era of anti-HER2 therapy.
As breast cancer diagnosis and treatment continued to evolve, researchers found that the four IHC indicators—ER/PR receptors, HER2, and the Ki-67 index—were highly correlated with breast cancer molecular subtypes. Consequently, clinical practice has generally used IHC results for these four markers as a surrogate for molecular classification, dividing breast cancer into Luminal A, Luminal B, HER2-positive, and triple-negative breast cancer (TNBC) subtypes. HR-positive disease accounts for the largest proportion of breast cancer molecular subtypes, and different treatment strategies are required based on the biological characteristics of each subtype.
HR-Positive Breast Cancer
From Endocrine Therapy to Precision Targeted Combinations
HR-positive breast cancer is the most common subtype, with endocrine therapy-based treatment strategies continuing throughout the course of the disease. From tamoxifen ushering in the era of endocrine therapy in 1977 to the emergence of aromatase inhibitors (AIs), selective estrogen receptor modulators (SERMs), and selective estrogen receptor degraders (SERDs), advances in endocrine therapies have broadly improved outcomes for patients with advanced HR-positive breast cancer. However, endocrine resistance remains a major barrier to further improving treatment efficacy. In recent years, as understanding of resistance mechanisms and therapeutic targets has deepened, precision treatment strategies aimed at overcoming endocrine resistance in HR-positive breast cancer have opened up a new landscape, continuously reshaping the treatment paradigm.
CDK4/6 Inhibitors Plus Endocrine Therapy: Transforming First-Line Treatment
The Cyclin D-CDK4/6 pathway is a key pathway driving cell-cycle progression in HR-positive breast cancer cells. CDK4/6 inhibitors block this pathway and prevent cells from transitioning from the G1 phase to the S phase, thereby effectively inhibiting tumor-cell proliferation and growth. Multiple clinical studies, including PALOMA-2, MONARCH-3, and MONARCH-2/7, have demonstrated that endocrine therapy combined with CDK4/6 inhibitors has become the standard first-line treatment for HR+/HER2-negative advanced breast cancer. The 2026 Chinese Society of Clinical Oncology (CSCO) Guidelines for Breast Cancer recommend an AI combined with a CDK4/6 inhibitor as a Level I recommendation for patients who have not previously received endocrine therapy. For patients whose disease has progressed following endocrine therapy, CDK4/6 inhibitors combined with fulvestrant can also significantly prolong progression-free survival (PFS).
Notably, as research findings on domestically developed CDK4/6 inhibitors have emerged, dalpiciclib, lerociclib, and trilaciclib? have all been approved in China and entered clinical practice. The emergence of these domestically developed agents has not only substantially improved drug accessibility and affordability but has also expanded clinical options through differentiated molecular designs, such as optimization of the myelosuppression profile and avoidance of potential hepatotoxicity, allowing physicians to make individualized treatment decisions based on patients’ baseline characteristics. In addition, the 2026 CSCO Breast Cancer Guidelines included kumociclib for the first time, the world’s first multi-target CDK2/4/6 inhibitor. This landmark update indicates that cell-cycle targeted therapy is moving from “broad dual-target” pathway blockade toward a new stage of “precision multi-target” coordinated inhibition.
PAM Pathway Inhibitors: Precisely Addressing Treatment Resistance
Hyperactivation of the PI3K/AKT/mTOR (PAM) pathway occurs in approximately 50% of patients with HR+/HER2-negative metastatic breast cancer and represents one of the important mechanisms of resistance to CDK4/6 inhibitors and endocrine therapy. A number of precision-targeted therapies have therefore been developed against this pathway. For patients with HR+/HER2-negative metastatic breast cancer who have previously received endocrine therapy and harbor PIK3CA mutations or PIK3CA/AKT1/PTEN alterations, PI3K and AKT inhibitors provide more precise treatment options.
Based on the results of the INAVO120 study, the triplet regimen of inavolisib combined with palbociclib and fulvestrant has been approved in China, providing a new treatment option for patients with HR+/HER2-negative locally advanced or metastatic breast cancer harboring PIK3CA mutations whose disease has developed endocrine resistance, including recurrence during or after adjuvant endocrine therapy.
Based on the CAPItello-291 study, the AKT inhibitor capivasertib combined with fulvestrant has also been approved in China, providing another treatment option for patients with HR+/HER2-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN alterations whose disease has progressed after at least one line of endocrine therapy in the metastatic setting, or who experienced recurrence during adjuvant therapy or within 12 months after completing adjuvant therapy.
Oral SERDs: A New Weapon Targeting ESR1 Mutations
The ESR1 gene encodes the ERα protein. ESR1 mutations can induce ligand-independent activation of ERα, alter its conformation, and potentially lead to endocrine therapy resistance in ER-positive breast cancer. ESR1 mutations are acquired mutations that emerge following endocrine therapy and occur in approximately 20%–40% of patients with metastatic breast cancer treated with AIs. Oral SERDs and other novel endocrine therapies precisely target ESR1 mutations, helping to overcome endocrine resistance.
The EMBER-3 study showed that imlunestrant monotherapy significantly prolonged PFS in patients with ESR1 mutations and achieved a clinically meaningful improvement in overall survival (OS), with a median OS of 34.5 months. The PFS benefit in the Chinese population was consistent with that observed in the global population. In patients with ESR1 mutations, the combination of imlunestrant and abemaciclib further prolonged median PFS to 11.1 months, with consistent PFS benefits in patients with ESR1 mutations previously treated with CDK4/6 inhibitors and those with co-mutations in ESR1 and the PI3K pathway. Imlunestrant has been approved in China, becoming the first—and currently the only—approved novel oral SERD in the country.
ADCs: A New Option in the Post-Endocrine Therapy Era
For patients who are no longer suitable for continued endocrine therapy, antibody-drug conjugates (ADCs) provide important treatment options. Following the publication of results from DB-04/06, TROPiCS-02, TROPION-Breast01, OptiTROP-Breast02, and other studies, several ADCs—including trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), datopotamab deruxtecan (Dato-DXd), and sacituzumab tirumotecan (sac-TMT)—have received approval in China for relevant indications, providing clinicians with a broader range of individualized treatment options.
From molecular subtyping to gene-guided precision treatment, the diagnostic and therapeutic paradigm of breast cancer is undergoing profound transformation. Looking ahead, precision treatment for HR+/HER2-negative breast cancer is expected to continue evolving in several directions:
1. A more refined “molecular map”: Innovation in precision treatment models — new classification systems such as the “Fudan four-subtype classification” of Luminal breast cancer are being explored to identify new strategies for overcoming treatment resistance.
New therapeutic targets — potential targets including FGFR mutations, CDK2, CDK7, and CDK9 are continuously being investigated.
2. A smarter “dynamic navigation system”: Liquid biopsy technologies, including circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), can be used to monitor treatment response, detect minimal residual disease, and identify resistance at an early stage.
3. A more powerful “intelligent brain”: Multidimensional data integration — integrating genomic, transcriptomic, proteomic, and other multi-omics data to construct precise prognostic models and guide individualized treatment decisions.
HER2-Positive Breast Cancer
Iterative Advances in Anti-HER2 Therapy
Since trastuzumab was approved in 1998, the development of anti-HER2 therapies has dramatically improved survival outcomes for patients with advanced HER2-positive breast cancer. From large-molecule monoclonal antibodies, including trastuzumab, pertuzumab, and margetuximab, to small-molecule TKIs, including lapatinib, neratinib, pyrotinib, and tucatinib, and then to HER2-targeted ADCs, including T-DXd, T-DM1, and trastuzumab duocarmazine, the expanding range of therapies has continuously reshaped the treatment landscape.
Today, anti-HER2 therapy encompasses three major categories—large-molecule monoclonal antibodies, small-molecule TKIs, and HER2-targeted ADCs—driving treatment into an increasingly precise and refined era of management for HER2-positive breast cancer.
Triple-Negative Breast Cancer
From the Chemotherapy Dilemma to Multiple Breakthroughs
Triple-negative breast cancer is the most aggressive breast cancer subtype and is associated with the poorest prognosis. For a long time, chemotherapy remained the main treatment option for advanced TNBC, but its efficacy was limited. To address this challenge, researchers have systematically explored the molecular heterogeneity of TNBC. With advances in precision medicine, multiple targeted and immunotherapeutic approaches have begun to emerge, offering new opportunities to improve outcomes for patients with advanced TNBC.
The Fudan Four-Subtype Classification Opens a New Chapter in Precision Treatment
In 2016, Professor Zhi-Ming Shao’s team proposed the “Fudan four-subtype classification.” In the following years, the team validated the classification and demonstrated that selecting targeted therapies based on molecular subtype represents an important foundation for precision treatment of TNBC.
PARP Inhibitors Provide a Precision Treatment Option for HER2-Negative Breast Cancer with gBRCA Mutations
Approximately 6.0% of patients with breast cancer harbor pathogenic germline mutations in BRCA1/2. The frequency of BRCA1/2 mutations is associated with age at diagnosis, family history of cancer, and molecular subtype. BRCA mutations lead to homologous recombination deficiency, while PARP inhibitors selectively eliminate tumor cells through a synthetic lethal mechanism.
Currently, several PARP inhibitors, including olaparib, talazoparib, and fluzoparib, have been approved in China and internationally for patients with HER2-negative metastatic breast cancer harboring germline BRCA mutations.
Compared with other breast cancer subtypes, TNBC is associated with increased tumor-infiltrating lymphocytes (TILs), higher PD-L1 expression, and greater genomic instability, giving it distinctive immune characteristics. Based on these unique immunological features, immune checkpoint inhibitors have opened a new chapter in the treatment of advanced TNBC. Following the publication of results from studies such as KEYNOTE-355 and TORCHLIGHT, PD-1/PD-L1 inhibitors including pembrolizumab and toripalimab, combined with chemotherapy, have demonstrated significant PFS improvements in PD-L1-positive patients and have received approval for relevant indications in first-line treatment of advanced TNBC.
ADCs Bring a Major Breakthrough to Advanced TNBC
The emergence of ADCs represents an important breakthrough for advanced TNBC, which has long relied on chemotherapy despite limited efficacy. SG, a Trop-2-directed ADC, was among the first to receive approval for patients with advanced TNBC who had previously received at least two systemic therapies, including at least one for metastatic disease.
Based on the OptiTROP-Breast01 study, sacituzumab tirumotecan has been approved in China for patients with unresectable locally advanced or metastatic TNBC who have previously received at least two systemic therapies, including at least one treatment for advanced or metastatic disease.
At the same time, T-DXd has also demonstrated promising activity in HER2-low TNBC. The emergence of multiple ADCs is profoundly reshaping the treatment landscape of TNBC.
Conclusion
Molecular subtyping has established the foundation for “treating breast cancer according to subtype.” Through stratification based on key biomarkers including ER, PR, HER2, and Ki-67, clinicians can more precisely classify tumor biology and establish an evidence-based foundation for standardized treatment strategies tailored to different breast cancer subtypes.
With deeper exploration of breast cancer resistance mechanisms and signaling pathways, the treatment paradigm is evolving from single-agent endocrine therapy toward precision treatment involving targeted combinations and strategies designed to overcome resistance.
From a “one-size-fits-all” approach to subtype-based treatment, and from subtype-based treatment to gene-guided precision therapy, every transformation in breast cancer diagnosis and treatment represents a deeper commitment to protecting human health.
Seeing the subtle allows us to foresee the far; by understanding the microscopic world, we can open up new possibilities for the future.
Professor Yongmei Yin
Jiangsu Provincial People’s Hospital
