Real-World Data Reveals Gap Between Guidelines and Practice in HER2+ Breast Cancer Care

The standard of care for HER2+ metastatic breast cancer is taxane, trastuzumab and pertuzumab (THP), followed by maintenance therapy, but many patients don’t receive this guideline-recommended first-line treatment. Now a new study by Cleveland Clinic researchers sheds light on how often patients receive alternative therapies, and why.

The large, real-world retrospective study found that a little more than a third of patients received standard of care, which was associated with significantly better outcomes. However, patients receiving alternative regimens were more likely to have recurrent disease or other risk factors that might explain both the treatment choice and worse outcomes, researchers noted.

The findings provide support for considering newer antibody-drug conjugates like trastuzumab dreuxtecan earlier in the course of treatment, said Cleveland Clinic medical oncologist Azka Ali, MD, senior author on the study.

“We’ve got a first-line standard of care, but are patients even getting it in the real world?” Dr. Ali asks. “And if they’re not getting it because they’re recurrent breast cancers or can’t tolerate chemotherapy, that could be a reason they should be getting a more novel approach like an antibody drug conjugate.”

Nearly two-thirds of patients receive alternative therapy

A collaboration with AstraZeneca Pharmaceutical, the study analyzed information from the Flatiron Health database, including 3,277 patients who were treated at more than 280 oncology clinics across the United States. Around 75% of the patients were treated in community-based settings. The analysis included patients with stage 4 HER2+ breast cancer who received first-line treatment between 2015 and 2024.

Only 35% of patients received the guideline-recommended THP as a first-line treatment, while 65% received an alternative therapy.

Outcomes for standard of care were significantly better. The median time to third-line treatment or death was 30 months for THP, compared to 17 months for alternative regimens, while median progression-free survival after second-line treatment was 26 months with THP, compared to 19 months with the alternative.

“You would expect the vast majority would get the standard first-line treatment, so then we embarked upon understanding why that might be,” Dr. Ali says.

Recurrent disease, older age linked to alternative approach

Researchers identified several reasons for the difference. A key factor was the disease itself: Fifty-seven percent of patients in the alternative group had recurrent cancer, versus 34% in the standard care group.

“If they just got a similar treatment in the last year or a couple of years ago, it’s completely reasonable to go with something different, which could be an alternative regimen,” says Dr. Ali.

Patients receiving alternative therapy also tended to be older, were more likely to have HR+ status and more likely to have brain metastases, Age, pre-existing conditions like neuropathy, concerns about side effects or overall frailty could be reasons why chemotherapy was unsuitable for some patients in this group,

Next, the team plans to analyze alternative regimens in more detail and incorporate additional patient and disease factors to better understand treatment patterns and outcomes.

“We need to continue to do real-world type analyses to really see how patients are getting treatment,” Dr. Ali says.

The study, “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 does advisory and consulting work for AstraZeneca.