ADCs in Breast Cancer: Shaping the Future of HER2 and TROP-2 Targeted Therapy

Antibody drug conjugates (ADCs) represent a key cornerstone in treatment of early or metastatic breast cancer with HER2-alterations, demonstrating significant improvements in response, survival, and safety. With the increasing efficacy of ADCs in HER2-positive breast cancer, there is ongoing debate over optimal combinations and sequencing, and research into expanding use for other subtypes.

At the 2025 San Antonio Breast Cancer Symposium, experts discussed the evolving role of ADCs in breast cancer care, covering their use in early-stage disease and optimal sequencing in metastatic settings.

ADCs

ADCs are a type of targeted therapy capable of honing in on specific antigens on tumor cells, such as HER2 or TROP-2. ADC molecules are composed of 3 key parts: an antibody, a payload, often topoisomerase I inhibitors, or microtubule inhibitors like emtansine; and a linker to connect the antibody to the payload, which can be cleavable or non‑cleavable.¹

After the antibody binds to the antigen on the tumor cell surface, the ADC–antigen complex is internalized into the cell and the drug is released from the linker, leading to the payload release.¹

“Because ADCs localize the payload to tumor cells, we can broaden that therapeutic window, allowing potent agents to be used with better tolerability,” explained Sybille Loibl, MD, associate professor of obstetrics and gynecology at the Goethe University of Frankfurt. “That widening of the therapeutic index underlies many of the efficacy gains that we're now seeing with modern ADCs.”¹

Although ADCs are intended to have high selectivity for target antigens, some ADCs (eg, T‑DXd) have a membrane‑permeable payload that can diffuse out of the target cell to kill neighboring cells, including those with lower antigen expression. Referred to as the “bystander effect,” this may improve efficacy against heterogeneous disease.¹

As of 2025, there are 4 approved ADCs indicated for treatment of patients with HER2 breast cancers across disease settings. Trastuzumab emtansine (T-DM1, Kadcyla; Genentech) was the first ADC to receive FDA approval in 2013, followed by trastuzumab deruxtecan (T-DXd, Enhertu; Daiichi Sankyo) in 2019, sacituzumab govitecan (SG, Trodelvy; Gilead Sciences) in 2020, and, most recently, datopotamab deruxtecan (Dato-DXd, Datroway; AstraZeneca) in 2025.¹

HER2-Targeting ADCs

In HER2-positive (HER2+) early breast cancer, various trials have shaped the current treatment landscape in the post-neoadjuvant setting—a crucial point for optimizing long-term outcomes in high-risk early breast cancer. Landmark trials have established the benefit of HER2-targeting ADCs such as T-DM1 and T-DXd in reducing recurrence, which is highly driven by presence of HER2-positivity.¹

T-DM1 in the post-neoadjuvant setting was evaluated in the KRISTINE trial (NCT02131064),² a randomized, multicenter, open-label trial which helped to clarify the safety and efficacy of T-DM1 plus pertuzumab in this setting for patients with HER2+ early breast cancer. The data showed about a 50% improvement in invasive disease-free survival (IDFS) for T-DM1 compared to trastuzumab. This benefit translated into improved overall survival (OS; hazard ratio 0.66, absolute difference 4.7%).¹

Pathologic complete response (pCR) was a key end point in the trial and is a critical indicator of negative prognostic factor for recurrence in breast cancer in clinical trials. The KRISTINE trial showed that the pCR rate with T-DM1 plus pertuzumab was not significantly improved compared with the standard-of-care regimen (anthracycline-free chemotherapy). Hormone receptor-positive (HR+)/HER2+ tumors consistently showed lower pCR rates than HR-negative tumors, which has also been observed in other clinical trials.¹

T-DM1 remains the standard of care for many of these non-pCR patients, based on robust evidence showing improved IDFS and OS compared to trastuzumab alone.¹

T-DXd represents another ADC in the breast cancer therapeutic landscape and has multiple approved indications for metastatic disease and is currently being investigated in neoadjuvant (DESTINY‑Breast11, NCT05113251)³ and post-neoadjuvant (DESTINY‑Breast05, NCT04622319)⁴ treatment of HER2+ early breast cancer.¹

In treatment of heavily pretreated patients with early breast cancer, T-DXd demonstrates high responses and improved survival. According to data from the DESTINY‑Breast05, post-neoadjuvant T‑DXd showed a superior IDFS benefit over T‑DM1 (~ 50% relative improvement) in patients with high‑risk residual HER2+ breast cancer without pCR, leading to possible future shifts in standard care.¹

In HER2+ metastatic settings, T-DXd continues to outperform T-DM1. The DESTINY‑Breast03 trial (NCT03529110)⁵ showed T-DXd had superior PFS and OS compared with T-DM1 in the second line.¹

In terms of safety, T-DM1 is generally well-tolerated with well-established side effects including fatigue, thrombocytopenia, transaminase elevations, and mild neuropathy. T-DXd was associated with higher rates of certain adverse events such as nausea and vomiting, stomatitis, constipation, peripheral sensory neuropathy, risk of interstitial lung disease (ILD), and risk of radiation pneumonitis. Overall, no previously unrecognized adverse events were observed with T-DXd in the early breast cancer trials, though effective AE management and thoughtful patient selection remain essential.¹

Trop-2 Targeting ADCs

TROP-2 targeting ADCs are agents that bind to the TROP-2 antigen, which is expressed in various solid tumors including breast cancer. As of 2025, SG and Dato-DXd are both approved for treatment of metastatic breast cancer, including HR+, HER2-negative (HER2–) populations, and triple-negative breast cancer that is refractory to standard therapies.¹

SG is a TROP-2-targeting ADC that delivers the cytotoxic payload SN-38 directly to TROP-2 expressing tumor cells to induce apoptosis. In the TROPICS-02 trial (NCT03901339),⁶ SG showed improvement in PFS and overall survival OS in heavily pretreated HR+, HER2– metastatic breast cancer compared with treatment of physician's choice. SG led to high intracranial response rates observed in phase 0 and real-world studies, which is attributed to SG’s pH-sensitive linker and central nervous system (CNS)-penetrant SN-38 payload.¹

“The unique linker and payload of SG may facilitate better penetration and activity in brain metastases, demonstrated in preclinical and early-phase clinical data,” said Loibl.¹

Median OS data were also favorable; patients with CNS metastases achieved more than 30 months of survival, with response rates reaching 50% in some cohorts. These findings highlight SG’s meaningful intracranial activity and its emerging role in a population historically associated with poor outcomes.¹

Common toxicities associated with treatment include neutropenia and gastrointestinal symptoms such as nausea, vomiting, and diarrhea, with growth factor support often required for patients at higher risk. Additional AEs may include hair loss and fatigue.¹

Dato-DXd is the most recently approved ADC for patients with unresectable or metastatic, HR+/HER2- (IHC 0, IHC1+ or IHC2+/ISH-) breast cancer who have received prior endocrine-based therapy and chemotherapy. The TROPION-Breast01 trial (NCT05104866),⁷ which supported Dato-DXd’s approval, tested Dato-DXd in patients who had previously received 1 or 2 lines of chemotherapy for metastatic disease compared to the physician’s choice of chemotherapy.¹

The trial demonstrated a median PFS of 6.9 months with Dato-DXd compared with 4.9 months in the chemotherapy arm, along with a longer time to subsequent therapy among patients receiving Dato-DXd. Notably, clinical activity was observed regardless of prior CDK4/6 inhibitor exposure. Although no statistically significant OS benefit was seen, this may be attributable to the higher proportion of patients in the chemotherapy arm who received subsequent ADC therapy after completing the trial.¹

Stomatitis emerged as the most common adverse event, although most cases were low grade and manageable with supportive measures such as mouthwash or cold therapy. Mild ocular surface effects, including dry eye and keratitis, were also reported. Notably, unlike T-DXd, Dato-DXd was not significantly associated with interstitial lung disease (ILD), a key safety concern seen with other deruxtecan-based ADCs.¹

Dato-DXd is now recognized as an additional TROP-2–targeting ADC for patients with metastatic HR+/HER2– breast cancer and is frequently considered for individuals who have already received CDK4/6 inhibitors and multiple lines of chemotherapy. However, the optimal sequencing of Dato-DXd relative to other ADCs—such as SG or T-DXd—continues to evolve, with ongoing studies and real-world evidence helping to define its place in therapy.¹

Sequencing ADC Therapy in Metastatic Breast Cancer

As the therapeutic landscape expands, questions around sequencing have become increasingly central. Pharmacists are now considering not only what to give, but when and to whom. Key issues include identifying which patients should receive more aggressive therapy upfront and who might safely begin with traditional regimens.¹

Historically, first-line therapy has been well established: trastuzumab, pertuzumab, and a taxane. Following progression, T-DM1 became the standard second-line option; however, emerging data have reshaped this paradigm by positioning T-DXd as a potential earlier-line therapy. This shift raises the question: should T-DXd be used for all patients in the first line?¹

“How do we make this decision of who to escalate treatment with T-DXd and pertuzumab that in the first line setting?” posed Reshma Mahtani, DO, medical oncologist at Baptist Health Miami Cancer Institute and chief of breast medical oncology at Baptist Health Wellness and Medical Complex in Florida. “We could use clinical factors—such as CNS disease, significant visceral disease, or progression in the early-stage setting—and of course, we need biomarkers here.”¹

Biomarkers such as HER2DX and early ctDNA dynamics are being explored to refine selection. ctDNA, in particular, is generating considerable interest as a tool for monitoring treatment efficacy in real time. Dynamic changes in ctDNA could potentially signal early response or resistance, enabling clinicians to adjust therapy before radiographic progression. However, this is not yet definitive.¹

As sequencing becomes more complex, several guiding principles are emerging. Retrospective data suggest that the greatest benefit is often achieved with the first ADC exposure, while subsequent ADCs can still produce meaningful responses. Clinical factors such as early relapse, visceral or CNS involvement, and high tumor burden may favor earlier escalation to an ADC like T-DXd. Conversely, patients with slowly progressive or lower-risk disease may still be candidates for traditional regimens first.¹

“Taking all these issues into consideration, ineligible patients will likely still have access to T-DXd in the second line. The choice of capecitabine remains very appealing, but certainly patient preferences, clinical factors, and—hopefully in the future—predictive biomarkers could help us clarify this choice,” said Mahtani.¹

Despite rapid progress, numerous questions remain and ongoing clinical trials and real-world evidence will be critical for defining optimal sequencing strategies. Ultimately, the field continues to move toward a more personalized, risk-adapted approach that aims to maximize efficacy while preserving quality of life for patients.

REFERENCES

1. Waks A, Loibl S, Mahtani R, et al. Educational Session 6: ADCs in the Clinic. Presented at: SABCS 2025. December 9-12, 2025. San Antonio, TX

2. A study evaluating trastuzumab emtansine plus pertuzumab compared with chemotherapy plus trastuzumab and pertuzumab for participants with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Clinicaltrials.gov. Updated July 2, 2019. Accessed December 11, 2025. https://clinicaltrials.gov/study/NCT02131064

3. Trastuzumab deruxtecan (T-DXd) alone or in sequence with THP, versus standard treatment (ddAC-THP), in HER2-positive early breast cancer. Clinicaltrials.gov. Updated November 18, 2025. Accessed December 11, 2025. https://clinicaltrials.gov/study/NCT05113251

4. A study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in high-risk HER2-positive participants with residual invasive breast cancer following neoadjuvant therapy (DESTINY-Breast05). Clinicaltrials.gov. Updated May 9, 2025. Accessed December 11, 2025. https://clinicaltrials.gov/study/NCT04622319

5. DS-8201a versus T-DM1 for human epidermal growth factor receptor 2 (HER2)-positive, unresectable and/​or metastatic breast cancer previously treated with trastuzumab and taxane [DESTINY-Breast03]. Clinicaltrials.gov. Updated October 21, 2025. Accessed December 11, 2025. https://clinicaltrials.gov/study/NCT03529110

6. Study of sacituzumab govitecan-hziy versus treatment of physician's choice in participants with HR+/​HER2- Metastatic Breast Cancer (TROPiCS-02). Clinicaltrials.gov. Updated October 21, 2024. Accessed December 11, 2025. https://clinicaltrials.gov/study/NCT03901339

7. A phase-3, open-label, randomized study of Dato-DXd versus investigator's choice of chemotherapy (ICC) in participants with inoperable or metastatic HR-positive, HER2-negative breast cancer who have been treated with one or two prior lines of systemic chemotherapy (TROPION-Breast01). Clinicaltrials.gov. Updated April 14, 2025. Accessed December 11, 2025. https://www.clinicaltrials.gov/study/NCT05104866