Real-World Data on Treatment Outcomes in HER2-Negative Breast Cancer

Enhertu (trastuzumab deruxtecan; T-DXd) worked better for patients whose tumors are hormone receptor (HR)-positive, helping them stay on treatment longer than those taking Trodelvy (sacituzumab govitecan; SG), across all HER2-negative groups, according to a news release from Caris Life Sciences.

Contrarily, for patients with HR-negative and HER2-null tumors, Trodelvy showed better results when used as the first treatment; for other patient groups, there was no clear advantage to starting with one drug over the other.

"With the industry absence of head-to-head trials between the two most commonly used antibody-drug conjgates in breast cancer, real-world evidence remains our best tool to explore key questions around treatment scheduling and comparative effectiveness in similar patient populations," Dr. George W. Sledge, Jr., Caris executive vice president and chief medical officer, said in the news release.

Can real-world data guide Enhertu versus Trodelvy choices in HER2-negative breast cancer?

Drawing on data from more than 4,000 patients, Caris’ real-world database revealed important differences that could guide clinicians in selecting therapies to improve care. The analysis, published in Breast Cancer Research, found that Enhertu and Trodelvy delivered comparable benefits in triple-negative breast cancer, emphasizing the importance of personalizing treatment by tumor subtype.

In patients with HER2-low, HER2–ultra-low, and HER2-null breast cancer, time on treatment with Enhertu decreased to 4.8, 4.1, and 3.5 months, respectively, as HER2 expression declined. In contrast, HER2 status had little effect on Trodelvy, with time-on-treatment of 3, 2.8, and 3.4 months. Patients with hormone receptor–positive, HER2-negative tumors had longer time on treatment with Enhertu (1,049 patients) than with Trodelvy (453 patients), even in the HER2-null group.

Among all HER2-negative patients receiving both antibody-drug conjugates, starting with Enhertu (547 patients) or Trodelvy (432 patients) led to similar cumulative time on treatment of 10.4 versus 10.8 months, respectively. However, in the HER2-null, HR-negative subset, starting with Trodelvy resulted in longer time on treatment (11.7 versus 7.4 months) and longer overall survival (19.7 versus 11.8 months).

“This study highlights the power of Caris to turn vast, real-world data into clinically actionable insights,” said David Spetzler, President of Caris. “Caris is leading the charge in precision medicine by combining advanced AI and vast real-world data to illuminate paths toward more personalized care. It's not just innovation; it's a reimagining of how science meets treatment.”

Molecular Profiling Guides HER2-Negative Metastatic Breast Cancer Treatment

Patient tumors underwent molecular profiling for HER2 status and hormone receptor status at Caris Life Sciences. Real-world clinical data were obtained from insurance claims and analyzed using standard statistical methods.

Of the patients evaluated, 45% had no HER2 protein (HER2-null), 34% had low HER2, and 21% had ultra-low HER2. Most patients received only one treatment (81%), while 19% received both.

The median age was similar across treatment groups. Reflecting higher rates of triple-negative breast cancer in Black women, more Black patients received Trodelvy than Enhertu. Patients receiving Trodelvy were more likely to have biopsies from the original tumor site, while those receiving Enhertu were more likely to have biopsies from metastatic sites.

“Our study provides important insight into personalized treatment strategies in HER2-negative metastatic breast cancer and warrants further validation in independent datasets or in randomized controlled trials,” wrote lead study author Dr. George W. Jr. Sledge in the study.

Dr. George W. Sledge Jr. is the executive vice president and chief medical officer at Caris Life Sciences.

“Our study provides important insight into personalized treatment strategies in HER2-negative MBC and warrants further validation in independent datasets or in randomized controlled trials,” concluded Sledge.

References

1. “New Study from Caris Life Sciences Validates Optimal Sequencing in Informing Therapy Choices for Breast Cancer Subgroups,” Caris Life Sciences. News Release. August 12, 2025.
2. “Comparison of trastuzumab deruxtecan and sacituzumab govitecan in HER2-negative metastatic breast cancer: a large real-world data analysis,” by Dr. Sledge, G., et al. Breast Cancer Res. August 11, 2025.

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