HER2DX prognostic value in older patients with HER2-positive early breast cancer: A correlative analysis from the RESPECT phase III trial.

532 Background: HER2DX, the first multigene assay specifically designed for HER2+ breast cancer, has demonstrated potential to guide treatment decisions. However, its validation in the context of de-escalated chemotherapy regimens, including trastuzumab monotherapy, in older patients remains limited. In the RESPECT trial (NCT01104935, JCO 2020), 1-year of trastuzumab monotherapy was shown to be a clinically meaningful adjuvant option compared to de-escalated chemotherapy and trastuzumab in older patients with HER2+ early breast cancer. This exploratory analysis of HER2DX within the RESPECT trial (Trans-RESPECT study) aimed to evaluate the assay's prognostic value. Methods: The RESPECT Phase III trial enrolled patients aged 70–80 years with stage I–IIIA HER2+ early breast cancer. Participants were randomized to receive trastuzumab monotherapy (H group) or trastuzumab plus chemotherapy (H+CT group). Chemotherapy regimens included paclitaxel monotherapy (35.1%), anthracycline/cyclophosphamide alone (22.9%), CMF (19.8%), docetaxel monotherapy (14.5%), or docetaxel-carboplatin (3.1%). Risk stratification into HER2DX low- or high-risk groups used both the standard 50 cutoff (scale 1-99) and an exploratory 32 cutoff, previously reported in the APT trial (Tolaney et al., Lancet Oncol, 2023). The primary endpoint was relapse-free survival (RFS), with secondary endpoints including overall survival (OS). Results: Among 275 patients in the RESPECT trial, 154 tumors (56.0%) were profiled using HER2DX (H group: 74; H+CT group: 80). Baseline characteristics of the profiled cohort mirrored those of the overall trial population. Most patients (92.9%) had a performance status of 0, 28.6% were older than 75 years, 53.2% were HR-negative, 80.5% had node-negative disease, and the majority had pT1c (41.6%) or pT2 (44.8%) tumors. Using the HER2DX 50 cutoff, 40 patients (26.0%) were classified as high risk, and 114 (74.0%) as low risk. RFS was higher in the HER2DX low-risk group compared to the high-risk group (hazard ratio [HR] = 2.02, 95% CI: 0.97–4.19), with 5-year RFS rates of 92% and 77%, respectively. OS was also superior in the HER2DX low-risk group (HR = 2.74, 95% CI: 1.18–6.36), with 5-year OS rates of 97% and 84%. Using the HER2DX 32 cutoff, 81 patients (52.6%) were classified as high risk, and 73 (47.4%) as low risk. In the H group, 3- and 5-year RFS were 97% and 94% in the low-risk group, compared to 87% and 81% in the high-risk group. In the H+CT group, 3- and 5-year RFS were 95% and 95% in the low-risk group, compared to 93% and 83% in the high-risk group. Conclusions: The HER2DX genomic risk score demonstrates prognostic value in older patients with HER2+ early breast cancer, including those treated with trastuzumab monotherapy. This assay may aid in identifying patients suitable for treatment de-escalation strategies. Additional analyses will be presented at the conference. Clinical trial information: NCT01104935 .