Meta-Analysis in The Lancet Oncology Validates HER2DX Prognostic Value in Early HER2-Positive Breast Cancer

• ‍First individual patient-level meta-analysis of HER2DX prognostic score across 11 international studies.
• Over 2,500 patients were included from neoadjuvant and adjuvant treatment settings.
• HER2DX independently predicts long-term outcomes and informs treatment decisions.

 REVEAL GENOMICS, S.L., a biotechnology company based in Barcelona focused on advancing precision oncology through biomarker innovation, today announced the publication of the study “HER2DX and survival outcomes in early-stage HER2-positive breast cancer: an individual patient-level meta-analysis” in The Lancet Oncology.

In the most comprehensive analysis to date of the HER2DX genomic test, investigators evaluated its prognostic utility across more than2,500 patients with early-stage HER2-positive (HER2+) breast cancer. Data from 11 international studies, including APT, ATEMPT, CALGB40601, DAPHNe, and PHERGain, were harmonized to assess the ability of HER2DX to stratify long-term risk and inform personalized treatment strategies in both neoadjuvant and adjuvant settings.

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A need for innovation in HER2+ prognosis and treatment

Despite major advances in therapy, there is still great uncertainty around how to best tailor systemic treatment for individual patients with early-stage HER2+ breast cancer. Current treatment decisions are often based on clinical and pathological features such as tumor size, nodal status, hormone receptor expression, and pathological complete response (pCR) following neoadjuvant therapy. However, these parameters are evaluated separately and fail to capture the underlying biological heterogeneity of HER2+disease.

This lack of integration limits the precision of current risk assessment tools and may lead to both over treatment and under treatment.

HER2DX was developed to address this unmet need. The test combines biological features such as immune activation, proliferation, HER2signaling, and luminal differentiation with clinical factors, offering a more nuanced and comprehensive understanding of tumor biology and prognosis.

About the study

This systematic individual patient data meta-analysis,registered in PROSPERO (CRD42025634137), followed PRISMA-IPD guidelines andi ncluded patients treated between 2005 and 2022. The primary endpoint was event-free survival (EFS), with overall survival (OS) as a secondary endpoint.For patients who received neoadjuvant therapy, outcomes were further analyzed by pCR status to better understand HER2DX’s value in this setting.

HER2DX delivers independent prognostic value

HER2DX consistently emerged as a strong, independent predictor of both EFS and OS. It provided additional prognostic insight beyond standard clinical-pathological factors and stratified patients across multiple clinical subgroups, including by stage, hormone receptor status, and response to therapy.

In multivariable models, HER2DX as a continuous score wasindependently associated with EFS (stratified hazard ratio [HR] per 10-pointincrease: 1.25; 95% CI 1.14–1.38; p<0.0001). Patients classified as low-risk had a 6-year EFS of 93.6% (95% CI 92.0–95.2), compared with 82.9% (95% CI80.0–85.5) for high-risk patients, representing an absolute difference of10.7%. This corresponds to a 2.6-fold higher risk of experiencing an event in high-risk compared to low-risk patients (stratified HR: 2.55; 95% CI 1.97–3.76;p<0.0001).

Similar results were observed when evaluating OS. The6-year OS rates for HER2DX low-risk and high-risk patients were 97.2% (95% CI95.9–98.5) and 85.6% (95% CI 83.4–88.0), respectively, representing an absolute difference of 11.6%. This translates into a 3.8-fold higher risk of death for high-risk versus low-risk patients (stratified HR: 3.77; 95% CI 2.50–5.68).

Clinical Implications

Key insights from the study highlight HER2DX’s value across the full treatment continuum in early-stage HER2+ breast cancer:

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• ‍Stage I disease (post-surgery): The HER2DX risk score provided significant prognostic information among 729 patients treated with upfront surgery. This can support decisions to de-escalate to paclitaxel-trastuzumab (TH) or even omit chemotherapy entirely in selected low-risk patients.‍
• Clinical stage I–II (treatment planning): HER2DX can inform the choice between primary surgery and neoadjuvant therapy by identifying patients with higher biological risk who may benefit from early systemic treatment.
•  Neoadjuvant therapy in stage II–III disease: The HER2DX risk score helps stratify prognosis before treatment, identifying patients who may be suitable for de-escalated neoadjuvant regimens such as THP, and those who may require more intensive strategies, such as TCHP.‍
• Adjuvant therapy after neoadjuvant treatment: In both patients with pathological complete response and those with residual disease, the HER2DX risk score supports refined adjuvant treatment decisions, helping to tailor intensity based on residual risk.

These findings underscore the potential of HER2DX to reduce overtreatment in low-risk patients and optimize care for those at higher risk, advancing a more personalized approach to HER2+ breast cancer management.

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Study leadership and expert commentary

The study was led by first author Guillermo Villacampa, Head of the Statistics Unit at the Vall d’Hebron Institute of Oncology (VHIO )and Data Science Manager at SOLTI. Senior authors include Dr. Sara M. Tolaney, Chief of the Division of Breast Oncology at Dana-Farber Cancer Institute, and Dr. Aleix Prat, Co-founder and Chief Scientific Officer of REVEAL GENOMICS,Director of the Clínic Barcelona Comprehensive Cancer Center, and Professor of Medicine at the University of Barcelona.

“This meta-analysisis the culmination of an unprecedented effort to bring together patient-level data across 11 studies in a consistent, rigorous manner,” said Guillermo Villacampa. “By applying statistical methods to harmonized clinical and genomic data to evaluate their association with efficacy outcomes, we have demonstrated that HER2DX can provide clinicians with reliable, individualized prognostic information that could improve decision-making in daily practice.”

“With more than 2,500 patients across diverse settings, this study provides robust evidence to support HER2DX adoption in routine clinical practice. It brings us closer to truly individualized therapy for HER2+ disease”, said Dr. Sara M. Tolaney, Chief of the Division of Breast Oncology at Dana-Farber Cancer Institute.

“HER2DX represents a major step forward in the prognostic stratification of HER2-positive breast cancer. By offering comprehensive and actionable risk estimates, HER2DX helps oncologists tailor treatment intensity to each patient. This new meta-analysis, together with the prior meta-analysis of the HER2DX pCR score published in Annals of Oncology in 2023, provides robust and complementary validation of the test’s clinical utility across the full spectrum of early HER2+ disease,”said Dr. Aleix Prat, Co-founder and Chief Scientific Officer of REVEAL GENOMICS.

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