Tailoring Treatment: Real-World Evidence Guides ADC Sequencing in Breast Cancer

A new study leveraging real-world data offers clinicians crucial insights into the optimal sequencing of antibody-drug conjugates (ADCs) for patients with HER2-negative breast cancer. The research, published in Breast Cancer Research and led by Caris Life Sciences, compared the effectiveness of trastuzumab deruxtecan (T-DXd; Enhertu) and sacituzumab govitecan (Trodelvy) in different tumor subtypes, providing a roadmap for more personalized treatment selection in the absence of head-to-head clinical trials.^1,2

The investigation, which drew from a large real-world database of over 4000 patients, found that sequencing decisions should be guided by the patient's specific tumor characteristics. The findings suggest that for patients with hormone receptor (HR)-positive tumors, T-DXd demonstrated superior efficacy, leading to longer treatment duration compared with sacituzumab govitecan. Conversely, sacituzumab govitecan showed better outcomes when used as a first-line therapy for patients with HR-negative and HER2-null tumors. For other subgroups, the study did not identify a clear advantage to initiating treatment with one ADC over the other.

Unlocking Actionable Insights from Real-World Data

The study addresses a critical gap in oncology—the lack of direct comparisons between competing therapies in a controlled trial setting.

“With the industry absence of head-to-head trials between the two most commonly used ADCs in breast cancer, real-world evidence remains our best tool to explore key questions around treatment scheduling and comparative effectiveness in similar patient populations,” said George W. Sledge, Jr, MD, executive vice president and chief medical officer at Caris Life Sciences, in a press release.¹

The use of large, patient-centric datasets allows researchers to examine treatment outcomes in a heterogeneous population, more closely mirroring the diversity seen in clinical practice than the often-stringent inclusion criteria of randomized controlled trials.

Advancing Precision Medicine in Triple-Negative and HER2-Null Cancers

A particularly notable finding from the study relates to patients with triple-negative breast cancer (TNBC). The results indicated that T-DXd and sacituzumab govitecan provided comparable benefits in this challenging-to-treat subgroup. This finding highlights the need for a highly personalized approach, as a "one-size-fits-all" strategy is unlikely to be optimal. Clinicians must consider a patient's full molecular profile and clinical history when making treatment decisions, as a simple TNBC diagnosis may not be sufficient to guide the most effective therapeutic choice.

The differentiation in outcomes for patients with HER2-null tumors further refines treatment selection. HER2-null status is a particularly challenging diagnosis, as these tumors lack a targetable HER2 expression. The study's finding that sacituzumab govitecan was more effective as a first-line treatment in HR-negative, HER2-null patients provides a clear and compelling clinical signal, potentially altering standard practice for this specific cohort. This level of granularity in treatment guidance is a hallmark of precision medicine.

REFERENCES:

1. New Study from Caris Life Sciences Validates Optimal Sequencing in Informing Therapy Choices for Breast Cancer Subgroups. News release. Caris Life Sciences. August 13, 2025. Accessed August 19, 2025. https://tinyurl.com/42mw6jyj

2. Sledge GW, Xiu J, Solzak JP, et al. Comparison of trastuzumab deruxtecan and sacituzumab govitecan in HER2-negative metastatic breast cancer: a large real-world data analysis. Breast Cancer Res. 2025 Aug 11;27(1):144. doi: 10.1186/s13058-025-02094-7.