Redefining HER2 in Breast Cancer: From Conventional Positivity to Low and Ultralow in the New Era of Antibody-Drug Conjugates

Article information

Cancer Res Treat. 2026;58(1):15-25

Publication date (electronic) : 2025 December 18

doi : https://doi.org/10.4143/crt.2025.1182

¹Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

²Cancer Research Institute, Seoul National University, Seoul, Korea

³Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

Correspondence: Seock-Ah Im, Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro Jongno-gu, Seoul 03080, Korea Tel: 82-2-2072-0850 E-mail: moisa@snu.ac.kr

Received 2025 October 29; Accepted 2025 December 18.

Abstract

Human epidermal growth factor receptor 2 (HER2) has evolved from a poor prognostic factor to one of the most impactful predictive biomarkers in oncology. The introduction of trastuzumab established HER2 as a binary determinant of therapy, with HER2 immunohistochemistry (IHC) becoming the treatment-guiding diagnostic assay. However, the emergence of antibody-drug conjugates (ADCs), particularly trastuzumab deruxtecan, has challenged this paradigm by demonstrating activity in tumors with low and even ultralow HER2 expression. This review outlines the evolution of HER2 testing, from its historical discovery and early assay variability to the ADC era, where categories such as HER2-low and HER2-ultralow have emerged. We highlight key challenges: poor reproducibility at the lower end of IHC scoring, instability of HER2 status across timepoints and between primary and metastatic tumors, and no consistent biological distinction between low, ultralow, and null. Efforts to improve reliability—including structured training, high-sensitivity assays, RNA-based methods, and artificial intelligence-assisted pathology—are summarized. Finally, we reconsider the therapeutic implications of ADCs, with the question of whether the benefit parallels HER2 expression or extends into HER2-null disease. HER2 exemplifies how biomarker interpretation evolves with drug development. As new ADCs target additional antigens, pathologists must balance trial-driven categories with biologic reproducibility to ensure diagnostics remain aligned with therapeutic advances.

Keywords: HER2; Breast neoplasms; Antibody-drug conjugates; Trastuzumab; Trastuzumab deruxtecan

Introduction

The discovery of human epidermal growth factor receptor 2 (HER2) amplification and overexpression in breast cancer revolutionized the field of oncology, transforming a poor prognostic factor into one of the most successful predictive biomarkers in the history of targeted therapy. The development of trastuzumab and subsequent HER2-directed therapies established HER2 as the most important biomarker in breast cancer treatment. Traditionally, pathologists classified patients into two categories: HER2-positive tumors, which could benefit from HER2-targeted antibody therapies, and HER2-negative tumors. However, recent advances in antibody-drug conjugates (ADCs), particularly trastuzumab deruxtecan (T-DXd), have challenged this classification (Fig. 1) by demonstrating efficacy in tumors with low or even ultralow HER2 expression.

Fig. 1.

Evolution of human epidermal growth factor receptor 2 (HER2) immunohistochemistry in breast cancer. Representative HER2 immunohistochemistry (IHC) categories (3+, 2+, 1+, 0) with corresponding in situ hybridization (ISH) results, illustrating the transition from a binary HER2-positive/negative system to the inclusion of low, ultralow, and null categories. DB, DESTINY-Breast.

This emerging paradigm necessitates a re-evaluation of HER2 as a biomarker, with implications not only for diagnostic reproducibility but also for therapeutic decision-making. In this review, we summarize the historical evolution of HER2 testing, current challenges in HER2-low and ultralow interpretation, and the clinical impact of ADCs that extend the therapeutic reach of HER2-targeted strategies.

Historical Background of HER2

In 1984, Robert Weinberg and colleagues reported an oncogene isolated from a rat brain tumor cell line [1]. The gene showed striking amplification and was named neu, after neuroglioblastoma. The following year, its human homolog was identified and published in back-to-back articles [2,3]. This gene was similar to, but distinct from, the erbB gene, which encodes the epidermal growth factor receptor (EGFR). Importantly, it was shown to be amplified in human breast cancer and salivary gland adenocarcinoma cell lines [2,4]. Based on its sequence homology with erbB-1 (EGFR), the gene was designated c-erbB-2 or HER2 [5].

At the same time, Dennis Slamon, a medical oncologist, analyzed fresh-frozen breast cancer tissues collected from patients using Southern blot assays [6]. He demonstrated that a subset of breast cancers harbored HER2 amplification and that these tumors were associated with poor clinical outcomes [6].

Unlike previously described oncogenes such as src or myc, HER2 encoded a receptor tyrosine kinase expressed on the cell membrane. This localization raised the possibility of therapeutic targeting with monoclonal antibodies. A murine monoclonal antibody against HER2 was subsequently developed, showing antiproliferative effects in human breast cancer cell lines [7]. In 1992, a humanized version of this antibody—later named trastuzumab—was produced [8], representing the first targeted agent directed against a receptor tyrosine kinase in oncology.

Following promising results from phase I and II clinical trials [9-12], the U.S. Food and Drug Administration (FDA) approved trastuzumab in 1998 for use in combination with paclitaxel in patients with metastatic HER2-positive breast cancer. A pivotal phase III trial demonstrated that trastuzumab plus standard chemotherapy significantly improved outcomes compared with chemotherapy alone, establishing trastuzumab as the first-line standard of care for HER2-amplified metastatic breast cancer [13]. These discoveries established HER2 as both a prognostic and predictive biomarker, setting a precedent for biomarker-driven oncology.

Early Days of HER2 Testing and Guideline-Driven Standardization of HER2 Testing

At the time of HER2 discovery, most analyses were performed using solid matrix methods such as Southern blot. Because reported rates of HER2 amplification varied widely, Dennis Slamon and pathologist Michael Press recognized the importance of the detection method itself. They compared Southern, Northern, Western blotting, and immunohistochemistry (IHC) on the same set of samples to allow direct comparison across platforms [14]. Their results showed that, in most cases, findings were concordant across methods.

IHC offered a particular advantage over other methods by visualizing HER2 protein expression specifically on tumor cells, avoiding the dilution effect from surrounding non-neoplastic tissue. However, major challenges soon became evident. One was variability introduced by tissue processing. When IHC was performed on fresh-frozen versus formalin-fixed, paraffin-embedded tissue, decreased immunoreactivity was consistently observed in the fixed samples. While this was less problematic for tumors with high-level HER2 amplification, it led to significant discrepancies in those with low to moderate expression. Another limitation was the difficulty of semiquantitative scoring of IHC signals. Notably, these early observations already anticipated the issues now central to the reproducibility of HER2-low and ultralow categories.

During the early clinical trials of trastuzumab, HER2 overexpression was assessed by IHC using antibodies such as 4D5 or CB11. At that time, no clear consensus existed regarding interpretation methods. The 1996 American Society of Clinical Oncology (ASCO) guideline even stated that data were insufficient to recommend HER2 testing in breast cancer and that such testing was unlikely to be clinically useful. After the FDA approval of trastuzumab in 1998, HER2 testing rapidly entered daily pathology practice. Without standardized protocols, variability persisted across laboratories, including the use of different antibody clones and inconsistent scoring thresholds. These factors contributed to significant discordance in HER2 testing results [15,16].

In this background, the need for standardized testing became evident. The College of American Pathologists (CAP) and the ASCO jointly developed practice guidelines to provide standardized criteria for HER2 testing. The first ASCO/CAP guideline, published in 2007 [17], was a landmark effort that addressed key challenges across the preanalytic, analytic and postanalytic phases of testing. Subsequent updates in 2013 and 2018 further refined these recommendations, and a summary of the guideline evolution is presented in Table 1 [18,19].

Table 1.

Evolution of ASCO/CAP guidelines for HER2 testing

During this period, the primary goal of HER2 testing was clear: to identify “HER2-addicted” breast cancers—tumors associated with poor prognosis but highly responsive to HER2-targeted therapies.

The New ADC Era: Redefining HER2

The evolution of HER2-targeted therapy initially expanded through dual-antibody blockade trastuzumab with pertuzumab targeting dimerization domain [20,21] and small-molecule tyrosine kinase inhibitors including lapatinib, neratinib, and tucatinib [22-24], and through the development of the first ADC, trastuzumab emtansine (T-DM1) [25,26]. However, these approaches remained effective only in tumors classified as conventionally HER2-positive in metastatic, neoadjuvant, and adjuvant settings, which at the time confirmed the belief that only tumors with strong HER2 expression or amplification could benefit.

In 2016, a novel HER2-targeted ADC, DS-8201a—now known as T-DXd—was developed [27]. Preclinical studies demonstrated potent antitumor activity, and subsequent clinical trials confirmed remarkable improvements in both progression-free survival (PFS) and overall survival (OS) in patients with metastatic HER2-positive breast cancer [28]. These results led to the FDA approval of T-DXd for patients with previously treated HER2-positive disease. The clinical trials and their key results are presented in Fig. 2.

Fig. 2.

Clinical development of trastuzumab deruxtecan (T-DXd) across human epidermal growth factor receptor 2 (HER2) expression levels in breast cancer. Summary of pivotal trials evaluating T-DXd in different clinical contexts: eBC, mBC, and heavily pretreated settings. DB, DESTINY-Breast; DFS, disease-free survival; ET, endocrine therapy; HR, hazard ratio; HR+, hormone receptor–positive; IDFS, invasive disease-free survival; mOS, median overall survival; mPFS, median progression-free survival; NE, not estimable; pCR, pathologic complete response; T-DM1, trastuzumab emtansine.

Mechanistically, T-DXd differs from T-DM1 in several key aspects. It has a higher drug-to-antibody ratio and a membrane-permeable payload, which together generate a pronounced bystander effect [29]. HER2-positive cells internalize the ADC, but the released cytotoxic payload can diffuse into neighboring HER2-negative cells, thereby extending therapeutic efficacy beyond strictly HER2-overexpressing populations [29,30]. This opened the door to testing T-DXd in cancers that were not HER2-positive by old criteria but still had some expression, the so-called “HER2-low” group.

The pivotal DESTINY-Breast04 trial, reported in 2022 [31], included patients with HER2-low breast cancer, defined by HER2 IHC 1+ or IHC 2+/in situ hybridization (ISH)-negative. T-DXd significantly improved both PFS and OS compared with the treatment of physician’s choice (median PFS, 9.9 vs. 5.1 months; hazard ratio, 0.50; 95% confidence interval, 0.40 to 0.63; median OS, 23.4 vs. 16.8 months; hazard ratio, 0.64; 95% confidence interval, 0.49 to 0.84). Shortly thereafter, the FDA approved T-DXd as the first targeted therapy for HER2-low metastatic breast cancer. Importantly, the trial utilized the anti-HER2 antibody clone 4B5 (Ventana, Roche Diagnostics), which was subsequently approved as the first companion diagnostic (CDx) for identifying patients with HER2-low disease eligible for T-DXd therapy.

The updated ASCO/CAP 2023 guideline was subsequently released [32]. While acknowledging the clinical importance of the DESTINY-Breast04 findings, the panel reaffirmed the 2018 criteria and concluded that it was premature to create new HER2-low category. Nevertheless, the guideline recognized the clinical implications of distinguishing IHC 0 from 1+ and provided best-practice recommendations. These included examination of HER2 IHC slides at high power when separating 0 from 1+, and consideration of a second pathologist’s review in cases near the threshold.

The HER2 continuum did not stop at HER2-low. In DESTINY-Breast06, patients with HER2-ultralow breast cancer (IHC 0 with faint membrane staining in ≤ 10% of tumor cells) were enrolled as a prespecified exploratory cohort [33]. In this population—metastatic hormone receptor (HR)–positive breast cancer previously treated with at least one line of endocrine-based therapy—treatment with T-DXd resulted in longer median PFS than chemotherapy (13.2 vs. 8.3 months; hazard ratio, 0.78; 95% confidence interval, 0.50 to 1.21). Thus, the clinical indication of T-DXd has effectively extended across a continuum of HER2 expression without a defined lower limit. Reflecting these results, the CAP released its updated protocol template for breast cancer biomarker reporting, which includes an option to record “membrane staining that is incomplete and faint/barely perceptible and present in ≤ 10% of tumor cells (0+ with membrane staining)” under the HER2 IHC-negative (score 0) category [34]. Based on this recent history, the introduction of HER2-low and HER2-ultralow categories was driven by clinical trial entry criteria rather than by biological redefinition.

Challenges of HER2-Low and -Ultralow

In this background, many pathologists have asked how prevalent HER2-low and -ultralow breast cancers are in real-world practice, and how well we are performing in their diagnosis. The incidence of HER2-low breast cancer has varied widely across studies, ranging from 31% to as high as 64.7% [35-41]. For HER2-ultralow, reported rates span from 10.6% to 29% [36,39-41]. Such broad variation underscores the substantial variability in diagnosing these categories.

Accordingly, many studies have documented substantial diagnostic discordance and interobserver variability in the assessment of HER2-low and -ultralow breast cancers. Furthermore, discrepancies were consistently more pronounced in the lower expression categories. For example, Robbins et al. [42] reported that IHC 0 cases showed only 25% overall percent agreement, with poor interrater reliability (Fleiss κ=0.49). Baez-Navarro et al. [43] similarly found absolute agreement in fewer than 5% of cases on first scoring, though reproducibility improved when categories were clustered, with the highest consistency observed when comparing IHC 0 versus all other groups.

Other series have reached the similar conclusion. Zaakouk et al. [44] reported that absolute agreement occurred in fewer than 10% of cases and was largely confined to strongly HER2-positive tumors, whereas cases with low-level HER2 expression showed only fair to moderate interobserver concordance; agreement improved markedly when 1+ and 2+ categories were combined. More recently, studies explicitly addressing the ultralow category highlighted even greater instability: Lv et al. [38] reported that nearly one-third of locally defined HER2-ultralow cases were rescored as HER2-null on central review, and Wu et al. [45] demonstrated that interobserver consistency between HER2-null and ultralow was very poor (Fleiss κ=0.23), with high agreement achieved in only 4% of cases. In the DESTINY-Breast06, among 349 patients scored as HER2 IHC 0 at local laboratories, central review reclassified 24% as HER2-low and 40% as HER2-ultralow [46].

Beyond observer-related variability, the instability of HER2 status between different samples from the same patient is another example of the intratumoral heterogeneity we have been dealing with for a long time. In a large multicenter study [37], roughly one-quarter of tumors scored as HER2-low on biopsy were reclassified as HER2-zero on resection, and vice versa. Similar findings emerged when comparing primary and metastatic disease: Hoda and McIntire [47] reported ~70% concordance, with shifts largely occurring between low, ultralow, and null categories, while Geukens et al. [48], in an autopsy study, demonstrated coexistence of HER2-low and HER2-zero metastases within most patients, including intra-organ heterogeneity.

Temporal changes add further complexity. Miglietta et al. found discordance rates of 26%-38% between primary tumors and relapse or residual disease, mostly driven by transitions between HER2-zero and HER2-low, particularly in HR-positive cancers [49,50]. Zhu et al. [51] extended these observations to HER2-2+ tumors, showing overall discordance above 40% between primary and recurrent samples.

Collectively, these studies highlight that HER2-low and ultralow are not only difficult to score consistently but also unstable across specimen type, disease stage, and treatment course, limiting their robustness as biomarker categories.

Attempts to Improve Reproducibility in HER2-Low and -Ultralow

Several approaches have been explored to improve reproducibility. Building on the ASCO/CAP 2018 framework, Farshid and colleagues proposed a scoring flowchart specifically focused on low-level HER2 expression, with attention to common pitfalls. These modules are now being incorporated into training resources and external quality assurance programs, with the aim that structured education can further enhance consistency in HER2-low reporting [52,53].

In a recent prospective proficiency test including 66 pathology centers and more than 650 individual assessments, overall accuracy was 86% [54]. Most errors reflected over-calling rather than under-calling of HER2, and technical factors—such as antibody choice and detection platform—were identified as major drivers of variability. While these concordance rates were higher than in early retrospective studies, they are still lower than the reproducibility previously achieved for HER2 3+ cases, underscoring the need for further optimization.

Other alternative approaches have also been explored. Chan et al. [55] developed a high-sensitivity HER2 assay that combines principles of IHC and ligand-binding techniques. The assay showed high accuracy with a reportable range in attomoles per square millimeter. Notably, more than 70% of IHC 0 tumors were above the quantifiable limit on this assay, raising questions about the validity of current categorical HER2 IHC scoring.

RNA-based approaches have also been pursued. Li et al. [56] demonstrated that HER2 RNA levels measured by RNAscope strongly correlated with protein expression but did not reliably distinguish between IHC 0, ultralow, and 1+ tumors. Baez-Navarro et al. [57] reported similar findings using the MammaTyper assay, which reclassified nearly 60% of IHC 0/ultralow cases as HER2-low by quantitative PCR. In a large cohort analyzed with Oncotype DX, HER2 mRNA scores were significantly associated with IHC-defined categories but significant overlap persisted [58].

Artificial intelligence (AI)–assisted digital pathology has also been explored as a tool to improve reproducibility at the lower end of HER2 expression. Wu et al. [59] demonstrated that an AI algorithm integrated with augmented reality microscopy significantly increased accuracy and consistency for distinguishing HER2 IHC 0 and 1+, particularly in heterogeneous tumors. Krishnamurthy et al. [60] validated a fully automated AI solution across multiple sites, showing improved interobserver agreement and higher accuracy for pathologists, especially in the 0 versus 1+ distinction. More recently, Aidt et al. [61] combined quantitative IHC with AI-based interpretation, achieving strong correlation with ground truth measurements and mapping intratumoral heterogeneity at high spatial resolution. Collectively, these studies suggest that AI can support pathologists by reducing variability in the low-expression range. While technical solutions may improve consistency, the larger question remains: do these categories capture true biology, or are they simply artifacts of how we score HER2?

Are HER2-Low and -Ultralow Distinct Biologic Subtypes?

The clinical significance of distinguishing between HER2-low and ultralow as biologically distinct categories remains uncertain. Across datasets, HER2-low tumors are more frequent in HR-positive breast cancer than triple-negative breast cancer, but PAM50 and RNA studies have not shown consistent separation from HER2-null once HR status is taken into account [50,62]. Some series reported slightly higher ERBB2 RNA or luminal-related gene expression, but there is significant overlap across groups and no clear prognostic significance was shown [63]. Long-term node-negative cohorts suggested better disease-free survival and OS in HER2-low compared to HER2-null [64], but this has not been reproduced in a larger registry cohort [65]. Overall, outcomes and clinicopathological features of HER2-low are conflicting and most differences disappear when adjusted for HR status.

For HER2-ultralow, several recent clinicopathologic studies found it resembles HER2-low more than HER2-null, but without unique molecular features or consistent prognostic differences [36,39,40]. No significant differences in TP53, PIK3CA, or PTEN mutation profiles were observed between HER2-ultralow and the other subgroups [39]. Real-world metastatic cohorts show comparable outcomes for ultralow and low, both distinct from null, only in terms of ADC eligibility rather than biology [66]. And we have already discussed how unstable HER2-low and -ultralow status are, shifting across timepoints and between primary and metastatic samples within the same patient [47,48,67]. Taken together, current evidence suggests HER2-low and ultralow are trial-driven entry categories, not biologically distinct entities.

ADC Mechanisms and the Question of HER2 Thresholds

The debate around HER2-low and ultralow as distinct biological categories ultimately comes back to their true therapeutic implications. The original HER2 test was designed to identify tumors addicted to HER2 signaling and therefore having poor prognosis but responsive to trastuzumab. In contrast, the mechanism of T-DXd has changed this notion, in part through its bystander effect, where the drug released from HER2-positive cells can affect adjacent HER2-negative cells. This led investigators to ask whether T-DXd efficacy follows an incremental benefit with increasing HER2 expression, and how low that expression can get while still having clinical benefit.

Previous trials showed that within HER2-low breast cancers, IHC 1+ and IHC 2+/ISH-negative cases showed similar responses to T-DXd [31,78], putting the practical value of distinguishing these categories. DESTINY-Breast06 trial partly resolved this by proving efficacy in HER2-ultralow breast cancers, sparing the pathologists from the need for discriminating ultralow, 1+, and 2+ [33].

By definition, only one tumor cell with faint HER2 membrane staining qualifies for HER2-ultralow, making the distinction between HER2-ultralow from HER2-null both laborious and subjective. In the DAISY trial, though patients with higher HER2 expression showed better response rate, efficacy of T-DXd extended not only to HER2-low but also to a subset of tumors classified as HER2-null, with a confirmed overall response rate of 29.7% [79], questioning the clinical value of differentiating HER2-null from the others. The upcoming results of DESTINY-Breast15 are expected to clarify outcomes in HER2-null tumors [80], which will ultimately determine whether HER2 testing thresholds remain relevant in the ADC era.

Emerging ADCs beyond HER2 and Implications for Pathologists

The remarkable success of T-DXd has accelerated the development of next-generation ADCs targeting diverse surface proteins beyond HER2 (Table 2) [71-80]. These novel agents are being tested across both HER2-negative and unselected breast cancer populations, with varying companion biomarker testing.

Table 2.

Antibody-drug conjugates beyond trastuzumab deruxtecan

For pathologists, this shift raises new challenges. CDx may not be mandated for all agents, but when required, reproducibility concerns familiar from HER2-low are likely to recur with these newer targets. The role of the pathologist therefore, extends beyond technical scoring to evaluating whether such low or ultralow thresholds have true biological meaning or mainly follow trial entry criteria.

Conclusion

The evolving understanding of HER2 biology illustrates how a single biomarker can redefine therapeutic landscapes across decades. The shift from a binary classification system toward recognition of HER2-low and ultralow categories reflects both technological advances and clinical necessity. Yet, challenges remain substantial: assay reproducibility at the low end of detection, lack of a gold standard for ultralow expression, and clinical uncertainty in selecting patients who may derive benefit from ADCs. Importantly, the therapeutic success of T-DXd underscores the need to align diagnostic practice with drug development, highlighting the dynamic interplay between pathology and clinical oncology.

Future directions will likely involve enhanced assay sensitivity, integration of artificial intelligence, and development of complementary biomarkers that go beyond HER2 IHC. The story of HER2 serves as a paradigm for biomarker evolution, illustrating how advances in diagnostics and therapeutics can converge to expand treatment opportunities and improve patient outcomes.

Notes

Author Contributions

Conceived and designed the analysis: Koh J, Im SA.

Collected the data: Koh J, Im SA.

Contributed data or analysis tools: Koh J, Im SA.

Performed the analysis: Koh J, Im SA.

Wrote the paper: Koh J, Im SA.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.

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HER2 test category	2007 ASCO/CAP	2013 ASCO/CAP	2018 ASCO/CAP
IHC criteria
IHC 3+ (positive)	Uniform intense membrane staining in > 30% of invasive tumor cells	Circumferential, intense, complete staining in > 10% of tumor cells	Circumferential, intense complete staining in > 10% of tumor cells
IHC 2+ (equivocal)	Weak to moderate, complete membrane staining in ≥ 10% of cells; or intense staining in ≤ 30% of cells	Incomplete and/or weak–moderate staining in > 10% of cells; or intense, complete staining in ≤ 10% of cells	Weak to moderate, complete staining in > 10% of tumor cells
IHC 1+ (negative)	Weak, incomplete membrane staining in any proportion of cells; or weak complete staining in < 10%	Incomplete faint/barely perceptible staining in > 10% of tumor cells	Incomplete faint/barely perceptible staining in > 10% of tumor cells
IHC 0 (negative)	No staining observed	No staining; or incomplete faint staining in ≤ 10% of tumor cells	No staining; or incomplete faint staining in ≤ 10% of tumor cells
ISH criteria
ISH positive	HER2/CEP17 ratio > 2.2	HER2/CEP17 ratio ≥ 2.0; or ratio < 2.0 with average HER2 copy number ≥ 6.0	HER2/CEP17 ratio ≥ 2.0 and average HER2 copy number ≥ 4.0 (group 1)
ISH positive	HER2/CEP17 ratio > 2.2		HER2/CEP17 ratio < 2.0 with average copy ≥ 6.0 (group 3)
ISH equivocal	HER2/CEP17 ratio 1.8-2.2	HER2/CEP17 ratio < 2.0 with average copy number ≥ 4.0 and < 6.0	Category removed in 2018
ISH negative	HER2/CEP17 ratio < 1.8	HER2/CEP17 ratio < 2.0 with copy number < 4.0	HER2/CEP17 ratio < 2.0 with copy number < 4.0 (group 5)

Antibody-drug conjugates	Target	Payload	Clinical trials	Phase	Indication	Key results	Reference
Datopotamab deruxtecan (Dato-DXd)	TROP2	DXd	TROPION-Breast01 (NCT05104866)	III	HR+ mBC	PFS, 6.9 vs. 4.9 mo (HR, 0.63; 95% CI, 0.52-0.76; p < 0.0001)	[68]
Datopotamab deruxtecan (Dato-DXd)	TROP2	DXd	TROPION-Breast01 (NCT05104866)	III	ET failure		[68]
	TROP2	DXd	TROPION-Breast02 (NCT05374512)	III	mTNBC 1st line (IO ineligible)	PFS, 10.8 vs. 5.6 mo (HR, 0.57; 95% CI, 0.47-0.69; p < 0.0001)	[69]
Sacituzumab govitecan	TROP2	SN-38	ASCENT (NCT02574455)	III	mTNBC	OS, 12.1 vs. 6.7 mo (HR, 0.48; 95% CI, 0.38-0.59)	[70]
	TROP2	SN-38	TROPiCS-02 (NCT03901339)	III	HR+ mBC	OS, 14.4 vs. 11.2 mo (HR, 0.79; 95% CI, 0.65-0.96)	[71]
	TROP2	SN-38	ASCENT 03 (NCT05382299)		mTNBC 1st line (PD-L1–)	PFS, 9.7 vs. 6.9 mo (HR, 0.62; 95% CI, 0.50-0.77; p < 0.0001)	[72]
	TROP2	SN-38	ASCENT 03 (NCT05382299)	III	mTNBC 1st line (PD-L1–)		[72]
SHR-A1811	HER2		HORIZON-Breast01	III	HER2+ mBC	PFS, 30.6 vs. 8.3 mo (HR, 0.22; 95% CI, 0.15-0.34; p < 0.0001)	[73]
Patritumab deruxtecan (HER3-DXd)	HER3	DXd	NCT02980341 (NCT05424835)	I/II	HR+ mBC	Confirmed ORRs	[74]
					mTNBC	HR+/HER2–/HER3-high or low, 30.1%
					HER2+ mBC	TNBC (all HER3-high), 22.6%
						HER2+ (all HER3-high), 42.9%
MGC018	B7-H3	Duocarmycin	NCT03729596	I/II		Ongoing trial across various advanced solid tumors	[75]
9MW2821	Nectin4	MMAE	NCT05216965, NCT05773937	I/II		Advanced TNBC: ORR, 43.8% (95% CI, 19.8-70.1)	[76]
PF-06647020	PTK7	Aur0101	NCT02222922	I		ORR 21% in TNBC	[77]
PF-06647020	PTK7	Aur0101	NCT02222922	I		Responders tended to have higher PTK7 expression by IHC	[77]