Precision therapy for driver gene mutations in breast cancer: Current landscape and future perspectives

Table 1 Major driver gene mutations and targeted therapy strategies in breast cancer

Gene/biomarker	Mutation type	Related pathway	Main subtype association	Targeted agent	Key clinical evidence
PIK3CA	Somatic hotspot mutations	PI3K/AKT/mTOR	HR+/HER2-	Alpelisib (PI3Kα inhibitor)	SOLAR-1 study: Significant PFS benefit[5]
ESR1	Acquired mutations	Estrogen signaling	HR+/HER2-	Elacestrant (SERD)	EMERALD study: Superior to standard endocrine therapy[6]
BRCA1/2	Germline/somatic mutations	Homologous recombination repair	TNBC, HR+/HER2-	Olaparib, talazoparib (PARP inhibitors)	OlympiAD, EMBRACA studies: PFS benefit[7,8]
AKT1	Somatic mutation (E17K)	PI3K/AKT/mTOR	HR+/HER2-	Capivasertib (AKT inhibitor)	CAPItello-291 study: Significant PFS benefit[9]
HER2 (ERBB2)	Somatic mutations	HER2 signaling	HR+/HER2- (non-amplified)	Neratinib (TKI, tyrosine kinase inhibitor)	SUMMIT basket trial: Demonstrated antitumor activity[10]

HR+: Hormone receptor-positive; HER2-: Human epidermal growth factor receptor 2-negative; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin; SERD: Selective estrogen receptor degrader; TNBC: Triple-negative breast cancer; PARP: Poly ADP-ribose polymerase; TKI: Tyrosine kinase inhibitor; PFS: Progression-free survival.

Table 2 Acquired resistance mechanisms and subsequent management strategies for major targeted therapies in breast cancer

Prior therapy	Category of resistance mechanism	Specific molecular event	Biological consequence	Potential subsequent strategy	Clinical evidence/considerations	Validation level
CDK4/6 inhibitors (e.g., palbociclib)	Cell cycle pathway alteration	RB1 gene loss/mutation	Loss of key downstream brake, uncontrolled cell cycle	Switch to chemotherapy; ADCs (e.g., sacituzumab govitecan)	Poor prognosis, reduced response to subsequent endocrine therapy[18]	Clinically validated
CDK4/6 inhibitors (e.g., palbociclib)	Upstream pathway activation	Acquired PIK3CA or AKT1 mutations	Activation of alternative pathways, bypassing G1 arrest	Combine with or switch to pathway inhibitors (e.g., alpelisib, capivasertib)	SOLAR-1, CAPItello-291 studies show PFS benefit[5,9]	Clinically validated
CDK4/6 inhibitors (e.g., palbociclib)	Other mechanisms	Cyclin E (CCNE1/2) amplification; CDK2 upregulation	Direct drive into S phase, independent of CDK4/6	Investigational CDK2 inhibitors; novel SERDs	Clear preclinical evidence, clinical trials ongoing[19]	Emerging clinical/preclinical
PI3Kα inhibitor (e.g., alpelisib)	Target up/downstream alteration	PTEN loss; AKT1 E17K mutation	Enhanced pathway signaling output	Switch to AKT inhibitor (capivasertib)	CAPItello-291 study confirms capivasertib efficacy[9]	Clinically validated
PI3Kα inhibitor (e.g., alpelisib)	Bypass activation	ERBB2/HER2, FGFR, MET amplification/overexpression	Reactivation of downstream signaling via RTKs	Corresponding RTK inhibitors (e.g., neratinib) in combination	Requires identification via NGS; mostly in trials[20]	Emerging clinical/preclinical
PARP inhibitor (e.g., olaparib)	HRR function restoration	BRCA1/2 reversion mutations	Restores HRR, abolishes “synthetic lethality”	Switch to platinum-based chemotherapy; DNA damaging agents	Common cross-resistance with platinum; clinical evidence[21]	Clinically validated
Selective ER degrader (e.g., elacestrant)	Continued ER activation	De novo or clonally expanded ESR1 mutations (e.g., Y537S)	Insensitivity to existing SERDs, constitutive activation	Switch to chemotherapy; explore next-gen SERDs or PROTACs	Different ESR1 mutations have varying SERD sensitivity[24]	Clinically validated
Selective ER degrader (e.g., elacestrant)	Bypass pathway activation	PIK3CA, AKT1 mutations	Provides ER-independent growth signals	Combine with PI3K/AKT/mTOR pathway inhibitors	A common mechanism for endocrine therapy resistance[26]	Emerging clinical

CDK4/6: Cyclin-dependent kinase 4/6; ADC: Antibody-drug conjugate; HRR: Homologous recombination repair; PROTAC: Proteolysis targeting chimera; RTK: Receptor tyrosine kinase; SERD: Selective estrogen receptor degrader; PFS: Progression-free survival; NGS: Next-generation sequencing; ER: Estrogen receptor; PARP: Poly ADP-ribose polymerase; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin.

Table 3 Core challenges in precision therapy for driver genes in breast cancer

Challenge dimension	Specific problem	Impact on clinical practice
Technology and management	Lack of standardization: Non-uniform gene coverage and bioinformatics pipelines across NGS panels	Poor comparability of results, affecting reliability of treatment decisions and clinical trial enrollment[31]
Technology and management	VUS interpretation dilemma: Interpretation of “VUS” highly dependent on expert experience	Leads to clinical decision hesitancy, potentially causing patient anxiety or missed treatment opportunities[32]
Tumor biology	Spatiotemporal heterogeneity: Significant clonal evolution between primary and metastatic sites, and pre-/post-treatment	Single biopsy fails to represent the whole tumor landscape, leading to treatment failure based on localized information[34]
Tumor biology	Complex resistance mechanisms: Involve on-target mutations, bypass activation, histological transformation, etc.	Makes subsequent treatment selection extremely complex, often requiring re-biopsy for dynamic assessment[35]
Clinical translation	Drug toxicity management: e.g., hyperglycemia with alpelisib	Affects patient quality of life and treatment adherence[11]
Clinical translation	Optimization of combination strategies and sequencing: Unclear optimal order of targeted agents	Difficult to maximize efficacy and delay resistance; most combinations remain exploratory[35]

NGS: Next-generation sequencing; VUS: Variant of uncertain significance.

Table 4 Future innovative therapeutic strategies to address current challenges

Current challenge	Future innovative strategy	Representative technology/drug class	Potential advantage and mechanism
Multi-mechanism resistance	ADCs	T-DXd, SG	Deliver high-potency cytotoxic agents precisely to tumor cells via a “biological missile” approach, potentially overcoming resistance from bypass activation, etc.
Tumor heterogeneity and drug targeting	Novel drug delivery systems	Nanocarriers, prodrugs	Increase drug concentration at tumor sites, enable tumor microenvironment-specific activation, thereby reducing systemic exposure and adverse effects

ADCs: Antibody-drug conjugates; T-DXd: Trastuzumab deruxtecan; SG: Sacituzumab govitecan.