Emerging Targeted Therapies in Breast Cancer: Expanding HER2-Low and TROP-2 Breakthroughs Require Pharmacist Knowledge and Vigilance

One of the most notable developments in breast cancer therapy is the emergence of antibody-drug conjugates (ADCs), particularly trastuzumab deruxtecan (Enhertu; Daiichi Sankyo, Inc/AstraZeneca Pharmaceuticals LP). This therapy has rapidly reshaped treatment for patients whose tumors were historically categorized as HER2-negative, a group that previously lacked effective targeted treatment options beyond endocrine therapy and traditional cytotoxic chemotherapy.^1,2

Breast cancer has traditionally been divided into HER2-positive and HER2-negative disease based on immunohistochemistry (IHC) and in situ hybridization (ISH). However, research data now show that approximately 50% to 60% of tumors express low levels of HER2 (IHC 1+ or 2+ with negative ISH), now termed HER2-low disease.¹ These cancers were previously treated as HER2-negative despite biologic differences that can now be therapeutically targeted.

Trastuzumab Deruxtecan Redefines HER2-Low Treatment

The original 2022 DESTINY-Breast04 trial (NCT03734029) was the first study to demonstrate a survival advantage with trastuzumab deruxtecan in patients with HER2-low metastatic breast cancer. In this phase 3 trial, treatment with trastuzumab deruxtecan resulted in a median overall survival of 23.4 months compared with 16.8 months with standard chemotherapy, representing a clinically meaningful improvement in survival.¹ Progression-free survival was also prolonged, with patients receiving trastuzumab deruxtecan experiencing nearly double the time before disease progression compared with chemotherapy.¹ These results led to rapid regulatory approval and major updates to national treatment guidelines.

More recent data from the 2024 phase 3 DESTINY-Breast06 trial (NCT04494425) further expanded the impact of this therapy by evaluating its use earlier in treatment for patients with hormone receptor (HR)–positive metastatic breast cancer with HER2-low or HER2-ultralow expression.² This study data demonstrated that trastuzumab deruxtecan significantly delayed disease progression compared with physician’s choice of chemotherapy and showed benefit in patients who had received fewer prior lines of therapy.² Importantly, this trial introduced the concept of HER2-ultralow disease, suggesting that the population eligible for targeted therapy may be even larger than previously recognized.

Trastuzumab deruxtecan represents a new generation of ADCs engineered with several pharmacological advantages. The drug has a high drug to antibody ratio, delivering a potent topoisomerase inhibitor directly to cancer cells. Additionally, its protease-cleavable linker enables intracellular drug release and produces a “bystander effect,” eliminating neighboring tumor cells with low HER2 expression.³ These characteristics help overcome tumor heterogeneity, a major challenge in breast cancer treatment.

This therapeutic modality introduces new opportunities and responsibilities for pharmacists, including monitoring for interstitial lung disease (ILD), managing infusion reactions, handling insurance authorizations, and educating patients on adherence and toxicity monitoring. Pharmacists also play an important role in integrating ADC therapies into evolving oncology treatment pathways.

Overall, trastuzumab deruxtecan represents one of the most significant breakthroughs in breast cancer treatment in the past decade. By redefining HER2 biology and expanding this drug therapy to a much larger patient population, it signals a broader shift toward ADCs as a foundation of future oncology care.

Sacituzumab Govitecan Extends ADC Reach Across Breast Cancer Subtypes

Trastuzumab deruxtecan has made an impact and changed how we treat HER2-low breast cancer, but it’s not the only ADC used today. Sacituzumab govitecan (Trodelvy; Gilead Sciences, Inc) is another ADC that is already part of the routine care. Although it does not target HER2, it targets TROP-2 and carries SN-38, an active form of irinotecan (Camptosar; Pfizer).

The phase 3 ASCENT trial (NCT02574455), with findings published in the New England Journal of Medicine, compared sacituzumab govitecan with standard chemotherapy in patients with heavily pretreated metastatic triple-negative breast cancer. The drug demonstrated significantly improved outcomes among patients, with progression-free survival of 5.6 months vs 1.7 months with chemotherapy and overall survival of 12.1 months vs 6.7 months, respectively, establishing the agent as a standard treatment option.⁴

The subsequent TROPiCS-02 trial (NCT03901339) evaluated sacituzumab govitecan in patients with HR-positive, HER2-negative metastatic breast cancer after prior endocrine therapy and chemotherapy. The trial data demonstrated similar improvements in outcomes, with median progression-free survival of 5.5 months compared with 4.0 months for chemotherapy, and median overall survival of 14.4 months vs 11.2 months, respectively.⁵ When viewed alongside DESTINY-Breast04 and DESTINY-Breast06 data, these findings underscore a clear shift in practice: ADCs are increasingly replacing traditional chemotherapy across multiple metastatic breast cancer subtypes.

Pharmacists’ Expanding Role in ADC Therapy

The rapid integration of ADCs into breast cancer treatment is reshaping the pharmacist’s clinical and leadership role in oncology. As HER2-low and HER2-ultralow classifications evolve, pharmacists must interpret molecular testing and guide therapy selection within complex guidelines. Beyond toxicity management, pharmacists support safe implementation by developing ILD monitoring strategies, standardizing growth factor use for neutropenia and diarrhea adverse effects, optimizing antiemetics, and educating care teams.⁶

These therapeutic agents deliver meaningful survival gains with a safer therapeutic profile than standard chemotherapy. Pharmacists influence outcomes through early toxicity recognition, adherence counseling, insurance navigation, and coordination of medication access, thus helping translate clinical trial efficacy into real-world effectiveness. As additional ADCs emerge, pharmacist involvement in formulary review and cost stewardship remains essential. Collectively, these agents reflect the shift toward precision-delivered cytotoxic therapy, with pharmacists central to optimizing safety, access, and patient outcomes.

References

1. Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690

2. Rugo HS, Cortés J, Diéras V, et al. Trastuzumab deruxtecan vs chemotherapy in HR-positive HER2-low metastatic breast cancer (DESTINY-Breast06). J Clin Oncol. 2024;17(24):4021. doi:10.3390/cancers17244021

3. Jalali P, Saeed A, Taher S, Saheed A. Trastuzumab deruxtecan: redefining precision oncology across HER2-driven cancers. Crit Rev Oncol Hematol. 2026;217:105019. doi:10.1016/j.critrevonc.2025.105019

4. Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485

5. Rugo HS, Bardia A, Marmé F, et al. Sacituzumab govitecan in hormone receptor–positive/Human epidermal growth factor receptor 2–negative metastatic breast cancer. J Clin Oncol. 2022;40(295):336-3376. doi:10.1200/JCO.22.01002

6. Cortés J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan versus chemotherapy in HER2-low metastatic breast cancer: safety and subgroup analyses. Lancet Oncol. 2023;24(1):74-86.