Novel HER2DX Assay Accurately Predicts Recurrence Risk and Pathological Response for Early-Stage HER2-Positive Breast Cancer


Research suggests a new HER2DX assay is potentially able to accurately predict risk of recurrence for patients with early-stage HER2-positive breast cancer.

Two HER2DX tests appeared to be effective in providing accurate estimates of recurrence risk and pathological complete response (pCR) likelihood among patients with early-stage HER2-positive breast cancer, according to results from a study published in EBioMedicine.

Specifically, potential exists for the HER2DX risk score to identify patients who would not benefit from additional therapies including pertuzumab (Perjeta), trastuzumab emtansine (Kadcyla), or neratinib (Nerlynx) because of favorable outcomes with chemotherapy and trastuzumab (Herceptin). When evaluated continuously, HER2DX risk score was significantly associated with distant relapse-free survival (DRFS; P = .0001). DRFS for the low-risk population, defined as patients with a 3-, 5- and 7-year DRFS, was 97.7% (95%, CI 95.7%-99.7%), 95.3% (95% CI, 92.5%-98.2%), and 94.3% (95% CI, 91.2%-97.4%), respectively. The 3-, 5-, and 7-year DRFS for the high-risk population was 90.4% (95% CI, 86.5%-94.4%), 84.3% (95% CI, 79.6%-89.3%), and 79.5% (95% CI, 74.3%-85.1%), respectively.

“HER2DX is a novel 27-gene expression and clinical feature-based classifier intended for clinical use for patients with early-stage HER2-positive breast cancer,” the investigators wrote. “The assay integrates clinical data with genomic data capturing tumor- and immune-related biology and predicts 2 different clinical endpoints, namely, long-term survival and likelihood of achieving a pCR.”

Eligibility criteria required patients to be aged 18 to 75 years and have surgically resected, HER2-positive breast cancer that was suitable for adjuvant chemotherapy. Node-positivity was also required, although patients could be node-negative if they had 1 of the following features: tumor size of 2 cm or greater, histological grade 3, presence of lympho-vascular invasion, Ki67 greater than 20%, age of 35 years or younger, or hormone receptor (HR) negativity.

Patients were randomized to either arm A or arm B between December 17, 2007, and October 6, 2013. Arm A received a chemotherapy regimen consisting of adriamycin at 60 mg/m2 plus cyclophosphamide at 600 mg/m or epirubicin at 90 mg/m2 plus cyclophosphamide at 600 mg/m2 every 3 weeks for 4 courses. This was followed by paclitaxel at 175 mg/m2 or docetaxel at 100 mg/m2 every 3 weeks. Trastuzumab was given every 3 weeks for 18 doses beginning with the first taxane dose. The treatment featured in arm B included docetaxel at 100 mg/m2 every 3 weeks for 3 courses followed by 600 mg/m2 of 5-fluorouracil, 60 mg/m2 of epirubicin, and 600 mg/m2 of cyclophosphamide every 3 weeks for 3 courses. Trastuzumab was started concomitantly with docetaxel and continued weekly for 9 weeks.

The study’s co-primary end points were to derive and validate a prognostic risk score, and a pCR likelihood score. Secondary end points focused on describing clinical-pathological features of HER2DX risk groups, exploring in-silico the association between HER2DX risk score and overall survival (OS) for HER2-positive early-stage breast cancer, and examining the value of ERBB2 mRNA in predicting HER2 status.

Researchers were able to collect and analyze clinical-pathological and gene expression data from 434 patients from the phase 3 Short-HER trial (NCT00629278). Patients had a mean age of 55.4 years and most had tumors that were 2 cm or less. Additionally, most patients were node-negative, HR-positive, and had grade 3 disease.

Additionally, findings indicated that HER2DX variables in the Short-HER trial were associated with positive risk outcomes including immune and luminal, as well as poor risk outcomes of proliferation, and tumor and nodal staging. Moreover, risk score was associated with disease-free survival (DFS; P = .002), with a 5-year DFS in the low-risk group of 97.4% (95% CI, 94.4%-100%) and 84.7% (95% CI, 77.4%-92.6%) in the high-risk group.

“We validate these 2 novel signatures, 1 for survival and 1 for predicting pCR, using multiple datasets, thus providing a high level of technical and clinical validation. Interestingly, the HER2DX risk score and HER2DX pCR likelihood score provide complementary information, opening an opportunity to better guide therapy through use of predictions of both response and survival,” the investigators concluded.


Prat A, Guarneri V, Pascual T, et al. Development and validation of the new HER2DX assay for predicting pathological response and survival outcome in early-stage HER2-positive breast cancer. EBioMedicine. Published online January 3, 2022. doi:10.1016/j.ebiom.2021.103801

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