HER2-positive metastatic breast cancer presents a particularly aggressive disease subtype, marked by overexpression of the human epidermal growth factor receptor 2 (HER2), which promotes tumor growth. The integration of targeted therapies, especially trastuzumab and pertuzumab, dramatically improved survival rates, but resistance and disease progression remain vexing challenges once first-line regimens fail.

The togetHER study, conducted across eighteen oncology centers in Greece from 2015 through 2018, retrospectively compiled clinical records of 122 adult female patients who began second-line treatment (2LT) for HER2+ metastatic breast cancer during this period. Importantly, these treatments predate the incorporation of newer agents like trastuzumab deruxtecan and tucatinib into second-line strategies, providing a baseline for evaluating past therapeutic approaches.

Among the cohort, a majority (68%) presented with recurrent metastatic breast cancer, highlighting the chronic and relapsing nature of this malignancy. A notable finding concerns the subset of patients retested for HER2 status at both early and metastatic stages. Approximately 27% experienced a shift from HER2-negative to HER2-positive status, highlighting the molecular heterogeneity and dynamic tumor evolution that can complicate treatment decisions.

Patient demographics at the outset of second-line therapy revealed a median age of 57 years. The hormonal receptor landscape showed over 63% of patients were hormone receptor-positive, emphasizing the dual-pathway involvement that oncologists must navigate with combination endocrine and anti-HER2 therapies.

Metastatic spread distribution provided a comprehensive view of disease burden: bone lesions were the most frequent at 56.6%, followed closely by lung metastases at 44.3%, liver involvement at 41%, and brain metastases affecting nearly 30% of patients. This metastatic dispersion underscores the systemic and multifaceted challenge faced in managing HER2+ breast cancer at advanced stages.

In treatment patterns, the near-universal use of anti-HER2 agents in first and second-line therapies (greater than 90%) affirms adherence to evolving standards of care. Nonetheless, usage rates dwindled slightly through third and fourth lines, signaling potential therapeutic limitations or shifts in clinical strategy as resistance develops.

Endocrine therapy administration remained conspicuously low, hovering between 5.9% and 12.3% across later lines. This low uptake may mirror the predominance of chemotherapy or targeted anti-HER2 regimens in later treatment stages, or possibly reflect patient-specific tumor biology that limits hormone therapy efficacy.

Conversely, chemotherapy use amplified in later lines, rising from 30.3% in second-line treatment to nearly 48% in third and fourth lines, highlighting the entrenched role of cytotoxic agents to combat advanced disease progression despite earlier targeted interventions.

The survival outcomes painted a sobering picture: median progression-free survival (PFS) declined with each treatment line, registering 7.7 months for second-line, 6.4 months for third-line, and only 5.6 months by the fourth line. This pattern elucidates the diminishing returns from conventional treatments over time.

Moreover, median overall survival across the study population was approximately 25 months post-second-line treatment initiation, a figure that reflects the limited life expectancy still faced by many despite therapeutic advancements.

One striking yet understudied aspect was the infrequent retesting of HER2 expression following the commencement of second-line treatment—only eight cases recorded such reassessment. This practice gap could have significant implications for tailored therapies, as tumor biology may further evolve under treatment pressure.

The clinical implications emerging from the togetHER study resonate beyond Greek oncology circles. They reveal persistent unmet needs despite guideline-adherent therapy, underscoring the urgency for innovative treatments to improve long-term outcomes for metastatic HER2+ breast cancer patients.

Recent advances such as antibody-drug conjugates and novel tyrosine kinase inhibitors have reshaped treatment algorithms elsewhere, but this retrospective Greek cohort provides a critical foundation against which future real-world outcomes can be benchmarked.

The study’s retrospective design, though limiting causal inferences, robustly reflects everyday clinical practice rather than controlled trial settings, lending valuable insights into patient management variability, drug utilization patterns, and survival metrics.

Understanding how metastatic HER2+ breast cancer adapts and resists therapy is crucial to design more effective sequential therapeutic strategies. The togetHER study’s comprehensive data coverage—from molecular retesting patterns to metastatic site prevalence—enriches this understanding.

Ultimately, this work calls for heightened integration of translational research with clinical care, promoting biomarker re-evaluation during treatment and broadening access to evolving therapeutic options.

As the oncology community builds upon these findings, the hope remains that precision medicine approaches, empowered by real-world evidence like the togetHER study, will meaningfully extend and improve the quality of life for patients confronting metastatic HER2-positive breast cancer.

Subject of Research: Real-world management strategies and clinical outcomes of metastatic HER2-positive breast cancer in Greece in the second-line setting and beyond.

Article Title: Real-world management strategies and clinical outcomes of metastatic HER2-positive breast cancer in Greece in the second-line setting and beyond (the togetHER study).

Article References: Korantzis, I., Koumarianou, A., Rapti, V. et al. Real-world management strategies and clinical outcomes of metastatic HER2-positive breast cancer in Greece in the second-line setting and beyond (the togetHER study). BMC Cancer 25, 1473 (2025). https://doi.org/10.1186/s12885-025-14791-9

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-14791-9

Keywords: HER2-positive breast cancer, metastatic breast cancer, second-line treatment, trastuzumab, pertuzumab, chemotherapy, progression-free survival, overall survival, endocrine therapy, real-world study