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

PHOENIX, Ariz. — April 30, 2025 — HonorHealth Research Institute’s new downtown Phoenix laboratory has produced its first study, centered on a promising new treatment for pancreatic cancer, one of the most aggressive and difficult to treat of all malignancies.

Study results were presented April 29 in Chicago at the annual meeting of the 58,000-member American Association for Cancer Research (AACR), the world’s largest professional organization of cancer investigators, caregivers and patient advocates.

Study findings indicate that a newly discovered drug, RMC-6236, also known as Daraxonrasib, is a powerful inhibitor of RAS (including KRAS, NRAS and HRAS). These are commonly mutated cancer-causing genes that drive the formation of many types of tumors, including pancreatic cancer.  This study evaluated the effectiveness of RMC-6236 in patient-derived pancreatic tumors harboring KRAS mutations.

New: Center for Translational Science

According to this initial study to emerge from the Research Institute’s new Center for Translational Science laboratory, RMC-6236, when combined with other proven pancreatic cancer drugs, is a promising new agent against RAS, particularly KRASG12X. Existing KRASG12C inhibitors are unable to target other mutations and often have the unintended result of making  patient tumors drug resistant.

“The fibrotic tumor microenvironment in pancreatic cancer exacerbates therapy resistance, and combining RMC-6236 with other therapies could overcome both intrinsic and acquired resistances,” according to Taylor Bargenquast, a clinical research technician and lead author of the study abstract, which she presented at AACR.

“These results demonstrate the efficacy of RMC-6236 when combined with other therapeutic agents in a pancreatic cancer model — a three dimensional model of pancreatic cancer cells derived from patient biopsies,” said Sunil Sharma, M.D., director of the Center for Translational Science and the senior author of the study abstract.

“The combination of RMC-6236 with standard chemotherapy and targeted therapies enhances its antitumor activity, suggesting a promising strategy for improving therapeutic outcomes in pancreatic cancer,” said Erkut Borazanci, M.D., another of the study’s authors, and medical director of the Institute’s Oncology Research Division.

52,000 Americans expected to die

Pancreatic cancer is the third-leading cause of cancer-related death in the U.S., after lung and colorectal cancers, and is expected to contribute this year to the deaths of nearly 52,000 Americans.

Contributing to this study — Evaluating the efficacy of RAS(ON) inhibitor RMC-6236 combined with chemotherapy and other targeted therapies in 3D models involving patients with KRAS-mutated pancreatic cancer — was the Phoenix-based Translational Genomics Research Institute (TGen), part of City of Hope.

The study suggests that human clinical trials are warranted to further evaluate the safety and effectiveness of RMC-6236.

For more about HonorHealth Research Institute clinical trials: call 833-354-6667; or emailclinicaltrials@Honorhealth.com.

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About the HonorHealth Research Institute
HonorHealth Research Institute is an international destination that is at the forefront of providing patients with a better quality of life through its clinical trials and innovative treatment options. Headquartered in Scottsdale, Arizona, the institute’s team of physicians and researchers collaborate with experts from across the nation to offer life-changing therapies, drugs and devices. At HonorHealth Research Institute, patients have access to tomorrow’s health innovations, today. Learn more at: HonorHealth.com/research.
 

Meeting

AACR Annual Meeting 2025

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