HER2DX Assay in HER2+ Breast Cancer
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High HER2DX genomic assay score was significantly associated with pathologic complete response (pCR) in patients with stage I to III HER2-positive breast cancer treated with neoadjuvant trastuzumab (Herceptin), pertuzumab (Perjeta), and paclitaxel (THP), according to final results from the single-arm phase 2 BiOnHER clinical trial (NCT05912062) presented at the 2025 ASCO Annual Meeting.
A total of 83 patients were categorized into HER2DX-low (35.0%), -medium (37.5%), and -high (27.5%) pCR score groups. The corresponding pCR rates were 13.3% (95% CI, 4.4%-31.6%), 51.6% (95% CI, 33.4%-69.4%), and 81.8% (95% CI, 59.0%-94.0%), respectively (odds ratio [OR], 32.60; P < .001).
Among patients with hormone receptor (HR)–negative disease, pCR was achieved in 78.6% of high-score patients and 0.0% of low-score patients. For those with HR-positive tumors, the pCR rates were 87.5% and 13.8%, respectively, in the high- and low-score subgroups. Although HR status was initially associated with pCR (OR, 0.125; P = .006), it lost statistical significance in multivariable analysis that included HER2DX scoring.
Baseline Ki-67 score (median, 35.0%; range, 0%-90%; OR, 1.02; P = .098) and tumor-infiltrating lymphocyte (TIL) level (median, 8.0%; range, 0%-60%; OR, 1.03; P = .003) were not significantly associated with pCR. Although day 8 post-treatment biopsies provided biologic insight, they did not enhance the predictive power of HER2DX beyond baseline. In patients with pCR, decreases in HER2DX score from day 1 to day 8 were associated with treatment effect and aligned with suppressed proliferation in the ERBB2 pathway.
“HER2DX is a robust predictor of pCR following neoadjuvant THP in stage I to III HER2-positive breast cancer, outperforming HR status. Baseline TIL [levels] and Ki-67 [score] were not predictive of pCR, and HER2DX day 8 data did not improve predictive performance,” lead study author Bartomeu Fullana Grimalt, MD, a breast oncology medical oncologist at Catalan Institute of Oncology in Barcelona, Spain, summarized in the conclusion of the poster presentation.
BiOnHER Trial Design
BiOnHER investigators enrolled patients with stage I to III HER2-positive (ERBB2+) breast cancer at Catalan Institute of Oncology-University Hospital of Bellvitge in Barcelona. Eligible patients were treated with neoadjuvant THP for a total of 15 weeks. Eligible patients received a loading dose of trastuzumab and pertuzumab (HP) followed by weekly paclitaxel in combination with HP administered every 3 weeks for 5 cycles. Tumor biopsies were obtained prior to treatment initiation on day 1 and again on day 8, following the loading dose of HP and before the initiation of paclitaxel.
Following neoadjuvant therapy, patients who did not achieve a pCR with THP were treated with adjuvant ado-trastuzumab emtansine (Kadcyla) for 14 cycles. Patients who achieved a pCR with THP continued adjuvant trastuzumab monotherapy for 1 year. Adjuvant pertuzumab was not permitted under Spain’s regulatory guidelines.
All biopsy samples, collected as both fresh-frozen and formalin-fixed paraffin-embedded tissue, were evaluated for HER2DX gene expression signatures. The study assessed the expression of 185 genes at both timepoints. Patients were stratified into HER2DX low-, medium-, or high-risk groups based on predefined genomic thresholds.
All patients underwent a paired significance analysis of microarrays that had a false discovery rate of less than 5%, as well as t-tests to assess changes in gene expression between day 1 and day 8. Logistic regression was used to identify associations between HER2DX scores and pCR (defined as ypT0/isN0).
The study’s primary end point was the association between HER2DX score and pCR at day 1. Secondary end points included HER2DX performance by HR status, baseline TIL levels, baseline Ki-67 score, and HER2DX score pCR prediction at day 8.
Baseline Characteristics
The median age at baseline was 58 years (range, 35-83). HR-positive disease was present in 67.5% of patients (n = 56), whereas 32.5% of patients (n = 27) had HR-negative tumors.
Most patients presented with early-stage disease, including clinical stage IA (19.3%), IB (43.4%), and IIB (26.5%). Fewer patients had stage III disease, with stage IIIA, IIIB, and IIIC reported in 3.6%, 6.0%, and 1.2% of patients, respectively.
Residual cancer burden (RCB) was evaluated at surgery. RCB 0 was observed in 45.8% of patients (n = 38), RCB I was seen in 21.7% of patients (n = 18), RCB II was reported in 25.3% of patients (n = 21), and RCB III was seen in 7.2% of patients (n = 6).
Gene expression analysis was performed in paired tumor samples from 79 of 83 patients (95.2%). Among enrolled patients, cT1-cT2 disease accounted for 89.2% of cases, and cN0 was observed in 62.7% of patients. The overall pCR rate was 45.8%, increasing to 54.2% when patients with ypT1miN0 disease were included.
Gene Expression Changes
In the total population, treatment with HP significantly decreased the expression of 81 genes—including CREB3L4, SPDEF, and MUCL1—and significantly increased the expression of 84 genes—including GPNMB, CD68, CD84, and CD4. The change in expression ratio of 38 genes from day 1 to day 8 (20.5%) was significantly associated with pCR, including in the S100A9 (P = .006), TRPV6 (P = .008), GPNMB (P = .013), and LY9 (P = .016) genes.
Reference
Bartomeu Fullana Grimalt, Fara Brasó-Maristany, Petit A, et al. HER2DX genomic test in HER2-positive breast cancer treated with 15 weeks of neoadjuvant paclitaxel, trastuzumab, and pertuzumab (THP): final analysis from the BiOnHER clinical trial. J Clin Oncol. 2025;43(suppl 16):607-607. doi:10.1200/jco.2025.43.16_suppl.607