ADCs in Breast Cancer: Shaping the Future of HER2- and TROP2-Targeted Therapy

Antibody-drug conjugates (ADCs) represent a key cornerstone in the 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 (HER+) breast cancer, there is ongoing debate over optimal combinations and sequencing as well as research into expanding use for other subtypes.¹

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.

Antibody-Drug Conjugates in Breast Cancer

ADCs are a type of targeted therapy that can home in on specific antigens on tumor cells, such as HER2 or TROP2. ADC molecules are composed of 3 key parts: an antibody, a payload (often topoisomerase I inhibitors or microtubule inhibitors such as ado-trastuzumab emtansine [Kadcyla; Genentech, Inc]), and a linker to connect the antibody to the payload, which can be cleavable or noncleavable.¹

After the antibody binds to the antigen on the tumor cell surface, the ADC-antigen complex is internalized into the cell and the linker is cleaved, releasing the payload.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 Sibylle Loibl, MD, an associate professor of obstetrics and gynecology at Goethe University Frankfurt in Germany.¹ “That widening of the therapeutic index underlies many of the efficacy gains that we're now seeing with modern ADCs.”

Although ADCs are intended to have high selectivity for target antigens, some ADCs, such as fam-trastuzumab deruxtecan-nxki (Enhertu; Daiichi Sankyo, Inc), 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 enhance efficacy against heterogeneous disease.¹

As of December 2025, 4 ADCs were approved for the treatment of patients with HER2+ breast cancers across various disease settings. In 2013, trastuzumab emtansine (T-DM1) was the first ADC to receive FDA approval, followed by trastuzumab deruxtecan (T-DXd) in 2019, sacituzumab govitecan-hziy (SG; Trodelvy; Gilead Sciences, Inc) in 2020, and datopotamab deruxtecan-dllnk (Dato-DXd; Datroway; Daiichi Sankyo, Inc) in 2025.¹

HER2-Targeting ADCs

In HER2+ early breast cancer, various trials have shaped the current treatment landscape in the postneoadjuvant 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 the presence of HER2 positivity.¹

T-DM1 in the postneoadjuvant setting was evaluated in the phase 3 KRISTINE trial (NCT02131064),² a randomized, multicenter, open-label trial that helped clarify the safety and efficacy of T-DM1 plus pertuzumab (Perjeta; Genentech, Inc) in this setting for patients with HER2+ early breast cancer. The data showed an approximate 50% improvement in invasive disease–free survival (IDFS) for T-DM1 compared with trastuzumab (Herceptin; Genentech, Inc), and 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 a negative prognostic factor for breast cancer recurrence 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, a finding also observed in other clinical trials.¹

T-DM1 remains the standard of care for many patients who do not achieve pCR, based on robust evidence showing improved IDFS and OS compared with trastuzumab alone.¹

T-DXd represents another ADC in the breast cancer therapeutic landscape. It has multiple approved indications for metastatic disease¹ and is currently being investigated in neoadjuvant (DESTINY‑Breast11 [NCT05113251])³ and postneoadjuvant (DESTINY‑Breast05 [NCT04622319])⁴ treatment of HER2+ early breast cancer.

In heavily pretreated patients with early breast cancer, T-DXd demonstrates high responses and improved survival. According to data from the phase 3 DESTINY‑Breast05 trial, postneoadjuvant 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 phase 3 DESTINY‑Breast03 trial (NCT03529110)⁵ showed that T-DXd had superior progression-free survival (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 adverse events (AEs) including fatigue, thrombocytopenia, elevated transaminase levels, and mild neuropathy. T-DXd was associated with higher rates of certain AEs 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 AEs were observed with T-DXd in the early breast cancer trials, although effective AE management and thoughtful patient selection remain essential.¹

TROP2-Targeting ADCs

TROP2-targeting ADCs are agents that bind to the TROP2 antigen, which is expressed in various solid tumors, including breast cancer. As of December 2025, 2 TROP2-targeting ADCs—SG and Dato-DXd—were 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 delivers the cytotoxic payload SN-38 directly to TROP2-expressing tumor cells to induce apoptosis. In the phase 3 TROPiCS-02 trial (NCT03901339),⁶ SG showed improvement in PFS and OS in heavily pretreated HR+/HER2- metastatic breast cancer compared with physician's choice of treatment. SG also led to high intracranial response rates, which were observed in phase 0 and real-world studies and 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,” Loibl said.¹

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

Common toxicities associated with SG 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- (immunohistochemistry [IHC] 0, IHC1+, or IHC2+/ISH-) breast cancer who have received prior endocrine-based therapy and chemotherapy. The phase 3 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 with the physician’s choice of chemotherapy.¹

The trial demonstrated a median PFS of 6.9 months with Dato-DXd vs 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 exposure to CDK4/6 inhibitors. 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 AE, 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 ILD, a key safety concern seen with other deruxtecan-based ADCs.¹

Dato-DXd is now recognized as an additional TROP2-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 up front and who might safely begin with traditional regimens.¹

Historically, first-line therapy for HER2+ metastatic breast cancer 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 as the first-line treatment for all patients in this population?¹

“How do we [decide which patients] to escalate [to] treatment with T-DXd and pertuzumab that in the first-line setting?” posed Reshma Mahtani, DO, a medical oncologist at Baptist Health Miami Cancer Institute and chief of breast medical oncology at Baptist Health Wellness and Medical Complex in Florida.¹ “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.”

Biomarkers derived from the HER2DX assay and changes in circulating tumor DNA (ctDNA) early in treatment are being explored to refine selection. In particular, ctDNA 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, although 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 such as 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 [Xeloda; Genentech, Inc] remains very appealing, but certainly patient preferences, clinical factors, and—hopefully in the future—predictive biomarkers could help us clarify this choice,” Mahtani said.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. https://sabcs.org/events/educational-session-6-adcs-in-the-clinic/

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