Despite clear clinical guidelines, most patients with HER2-positive (HER2+) metastatic breast cancer do not receive the recommended first-line treatment of taxane, trastuzumab, and pertuzumab (THP), a new study by Cleveland Clinic researchers reveals. The study highlights the frequency of alternative therapy use and the factors influencing treatment decisions.
The large, real-world retrospective analysis found that just 35% of patients received THP as first-line therapy, while the remaining 65% were treated with alternative regimens. Importantly, outcomes were significantly better for those receiving the guideline-recommended treatment. Median time to third-line therapy or death was 30 months for THP recipients, compared to 17 months for patients on alternative therapies. Median progression-free survival after second-line treatment also favored THP, at 26 months versus 19 months.
“The question is whether patients in the real world are actually getting the first-line standard of care,” said Dr. Azka Ali, Cleveland Clinic medical oncologist and senior author of the study. “If they’re not—often due to recurrent disease or inability to tolerate chemotherapy—it may justify the use of newer approaches such as antibody-drug conjugates earlier in treatment.”
The study, conducted in collaboration with AstraZeneca, analyzed data from the Flatiron Health database, covering 3,277 patients treated at over 280 oncology clinics across the U.S. between 2015 and 2024. About 75% of the patients received care in community-based settings.
Researchers identified key factors linked to the use of alternative therapies. Patients with recurrent disease were more likely to receive non-THP regimens—57% in the alternative group versus 34% in the standard care group. Age, hormone receptor (HR) status, brain metastases, pre-existing conditions, and concerns about chemotherapy tolerance also influenced treatment selection.
“If a patient recently received similar therapy, it makes sense to choose a different approach,” Dr. Ali noted. “But age, frailty, and other health conditions can also make standard chemotherapy challenging, prompting clinicians to consider alternative regimens.”
The Cleveland Clinic team plans to further investigate alternative therapy patterns and integrate additional patient and disease factors to better understand outcomes.
“Our goal is to use real-world data to see how treatments are applied outside clinical trials and to identify opportunities for improving patient care,” Dr. Ali said.
The study, titled “Long-term Outcomes of First-Line Guideline-Recommended Treatment Versus Alternative Regimens in HER2+ Metastatic Breast Cancer: A Retrospective Observational Study of US Electronic Health Records,” was presented at the San Antonio Breast Cancer Symposium in December 2025. Dr. Ali has advisory and consulting ties to AstraZeneca.
