HER2DX is a genomic test that provides prognostic (HER2DX risk score) and predictive information (pCR score) in HER2+ early BC. Here, we report an update of the results of the first ongoing decision impact study of HER2DX at Hospital Clinic of Barcelona. We conducted an observational, prospective, pilot, unicentric study, since Nov/21 (ongoing), to analyze the impact of HER2DX in clinical practice in early-stage HER2+ BC. Any medical oncologist of the Breast Unit could order the test. A survey was completed by the treating physician before and after receiving the result of HER2DX. The main objective was to assess the % of change in the therapeutic plan after obtaining the HER2DX report. We also assess the change in the physician´s confidence before and after the test. Due to the exploratory nature of the study, there was no sample size calculation. Descriptive statistics were used. We report the results after the inclusion of 128 pts (as of 27th of Jan/24). Median age was 54 (range 30-90) and 55% of pts were postmenopausal. Most pts had stage I (37%) or II (48%), grade 2 (51%) or 3 (42%), ductal histology (85%), hormone receptor positive (62%), median Ki67 of 35 (range 3-90) and median TILs of 12 (range 0-90). 77% of pts received neoadjuvant therapy and 23% upfront surgery. Any change in the treatment plan before and after the HER2DX result was observed in 71 of 128 (55%) of the cases. Among them, 34% (n=24) of pts escalated therapy (7/24 used more intense chemotherapy (CT), 8/24 added another antiHER2 and 9/24 escalated both CT and antiHER2). A de-escalation strategy was noted in 66% (n=47) of the pts who changed the therapy. Among them, 18/47 received less intense CT, 18/47 less anti-HER2 and 11/47 both less CT and antiHER2. In pts who de-escalated the antiHER2, 23/29 received less antiHER2 (i.e. avoidance of pertuzumab or neratinib) and 6/29 shortened the duration of trastuzumab. In a scale from 1 (very unconfident) to 5 (completely confident), the mean confidence of physicians improved after the test (3.8 vs 4.6, p=0.002). In this first prospective study, HER2DX impacted clinical care in early-stage HER2+ BC and improved the level of confidence of physicians.

In first-line metastatic HER2+ BC, the standard regimen of taxane-trastuzumab-pertuzumab (THP) is increasingly challenged by new therapies like antibody-drug conjugates. This shift accentuates the necessity for precise biomarkers to guide treatment decisions. Our study focuses on using HER2DX ERBB2 mRNA score to predict treatment responses and long-term prognosis, aiming to identify patients who would benefit more from escalation or de-escalation therapies. We evaluated 85 patients with advanced HER2+ BC from Hospital Clinic of Barcelona, IOB-QuironSalud and Hospital Universitario 12 de Octubre, treated with the standard THP regimen between 2010 and 2024. HER2DX analysis was performed on formalin-fixed paraffin-embedded tumor samples. We correlated HER2DX ERBB2 mRNA score as a continuous variable and as pre-defined categories (low, medium, high) with progression-free survival (PFS) and overall survival (OS) using Cox regression models. The distribution of low, medium, and high HER2DX ERBB2 scores in our cohort was 16.5%, 23.5%, and 60.0%, respectively. With a median follow-up of 44.2 months (0.72-162.5), our cohort consisted of hormone receptor-positive cases (64.7%), patients with visceral disease (70.6%), brain metastasis (14.1%), and de novo metastatic disease (50.6%). Median PFS and OS to THP regimen were 27.1 and 62.7 months, respectively. HER2DX ERBB2 score was significantly associated with both PFS and OS, particularly in the ERRB2-high group, which showed significantly better PFS (28.6 vs. 12.5 months; hazard ratio=0.45, 0.26-0.78, p=0.005) and OS (not reached vs. 29.8 months; hazard ratio=0.23, 0.12-0.44, p<0.001). All patients without progression over 5 years and no death over 8 years (n=4) had ERBB2-high disease. These associations persisted in multivariable analyses. The HER2DX ERBB2 mRNA score shows a significant association with improved survival in metastatic HER2+ BC patients treated initially with THP. Additional validation of the HER2DX ERBB2 score and integration of prognostic clinical factors might refine and optimize treatment strategies in this clinical setting.

The effectiveness of the HER2DX pCR-score in predicting pCR to anti-HER2 neoadjuvant chemotherapy (NACT) in patients (pts) with HER2+ BC in real-world clinical setting has not been thoroughly evaluated. This study aims to assess the performance of the HER2DX pCR-score in a clinical environment at a single institution. We analyzed standardized HER2DX pCR-scores from pts with stage I-III HER2+ BC receiving trastuzumab-based CT at the Hospital Clinic of Barcelona between Nov/21 - Jan/24. This cohort was not previously included in HER2DX validation datasets. The primary goal was to explore the association between HER2DX pCR-score groups and pCR, considering hormone receptor (HR) status, Ki67, TILs, grade, HER2 IHC (3+ vs. 2+), and the type of CT (single taxane vs. multi-agent). Logistic regression methods were employed for statistical analysis. We included 86 pts with a median age of 51.9 years. Median TILs were 15.0%, 62.8% were HR+, 48.0% had grade 3, 20.9%, 61.6% and 17.4% were diagnosed with stage I, II and III, respectively, and 67.4% were treated with multi-agent CT. The overall pCR rate was 64.0% (95% CI 53.9.-74.0). The distribution across HER2DX pCR-high, -medium, and -low groups was 46.5%, 20.9%, and 32.6%, respectively, and the distribution ofHER2DX risk high and low was 58.1% and 41.9%, respectively. Univariable analysis demonstrated a significant association between HER2DX pCR score and pCR (high vs. low, odds ratio = 5.4, p = 0.002). In the multivariable model, HER2DX pCR-score remained associated with pCR after adjustment by clinico-pathological variables and type of CT (high vs low, OR = 7.4, [95% CI 1.37-40.25]; p = 0.020). The pCR rates in the HER2DX pCR-low and pCR-high groups were 35.7% and 75.0%, respectively. The selection of multi-agent versus single-agent CT was strongly associated with the HER2DX risk group. The HER2DX pCR-score is significantly associated with pCR in pts with early-stage HER2+ BC undergoing anti-HER2-based NACT in a real-world setting. A low HER2DX pCR-score is consistently correlated with a reduced likelihood of achieving pCR, independently of the use of multiagent CT and clinico-pathological factors.

The value of the HER2DX genomic assay in patients with advanced HER2+ disease is currently unknown. Here, we evaluated the association of the information provided by the HER2DX assay with T-DM1 benefit and survival.

HER2DX is a prognostic and predictive assay in early-stage HER2+ BC based on clinical data and the expression of 4 gene signatures (immune, proliferation, luminal differentiation and HER2 amplicon), including ERBB2 levels. Here, we evaluated the ability of HER2DX to predict efficacy of a de-escalated, chemotherapy (CT)-free neoadjuvant regimen in HER2+/HR+ BC.

PREDICT is an online tool (https://breast.predict.nhs.uk/) designed to help make informed decisions about treatment following surgery for early invasive BC and estimates overall survival (OS). HER2DX is a prognostic test that integrates clinical data and gene expression from immune, proliferation, luminal differentiation and HER2 amplicon processes. Here, we explored the prognostic ability of HER2DX beyond the PREDICT tool.