Extended follow-up from the phase 3 RESPECT trial (NCT01104935) showed that the HER2DX genomic assay provided long-term prognostic information for older patients with HER2-positive early-stage breast cancer, and when combined with the HER2DX pathological complete response (pCR) score, it may help identify patients more likely to benefit from the addition of adjuvant chemotherapy.1

Findings published in Nature Communications showed that among evaluable patients (n = 154), 74.0% had tumors classified as low risk per HER2DX, and 26.0% had high-risk tumors. The rates of low- and high-risk tumors in the trastuzumab (Herceptin) monotherapy arm (n = 74) were 78.4% and 21.6%, respectively. These respective rates in the trastuzumab plus chemotherapy arm (n = 80) were 70.0% and 30.0%.

HER2DX Assay in HER2+ Early Breast CancerAn analysis of the RESPECT trial showed the HER2DX genomic assay provided long-term prognostic information in older patients with HER2-positive early breast cancer.Ten-year RFS and OS rates were improved in patients with low-risk HER2DX compared with those who had high-risk scores.In conjunction with the HER2DX pCR score, the HER2DX assay could help identify patients more likely to benefit from the addition of chemotherapy to adjuvant trastuzumab.

Between the 2 arms, patients with HER2DX low-risk scores achieved a 10-year relapse-free survival (RFS) rate of 77.9% compared with 68.0% among patients with high-risk scores (HR, 0.48; 95% CI, 0.23-1.01; P = .05). The 10-year overall survival (OS) rates were 85.9% and 69.7%, respectively (HR, 0.34; 95% CI, 0.15-0.80; P = .01). Notably, sensitivity analyses with censoring at 5, 6, 7, 8, 9, and 10 years demonstrated consistent RFS and OS outcomes between the low- and high-risk subgroups.

“This study shows that the HER2DX genomic assay provides long-term prognostic information in older patients with HER2+ early breast cancer treated with adjuvant trastuzumab with or without chemotherapy,” lead study author Kazuki Nozawa, MD, of the Department of Advanced Clinical Research and Development and Department of Breast Surgery at Nagoya City University Graduate School of Medical Sciences in Japan, and colleagues wrote in a publication of the data. “In this population, standard clinicopathologic features, including tumor size, nodal status, hormone receptor expression, and TILs, were not significantly associated with RFS or OS, highlighting the added value of genomic stratification by HER2DX.”

What were the previously reported primary findings from the RESPECT trial?

Findings published in the Journal of Clinical Oncology in November 2020 revealed that the RESPECT trial did not meet its primary objective, with trastuzumab monotherapy failing to demonstrate noninferiority to trastuzumab plus chemotherapy in the overall population.2

Patients treated with trastuzumab monotherapy (n = 135) experienced a 3-year disease-free survival (DFS) rate of 89.5% compared with 93.8% for those given trastuzumab plus chemotherapy (n = 131; HR, 1.36; 95% CI, 0.72-2.58; P = .51). Additionally, the 3-year RFS rates were 92.4% and 95.3%, respectively (HR, 1.33; 95% CI, 0.63-2.79; P = .53).

Investigators did note that at 3 years, the restricted mean survival time differed by –0.39 months (95% CI, –1.71 to 0.93) between the trastuzumab monotherapy arm and combination arm, highlighting the potential for trastuzumab monotherapy as an adjuvant option for select older patients with HER2-positive early breast cancer. However, these findings underscored the need for robust biomarkers to guide de-escalated therapy decisions in this population.1

What was the design of the RESPECT trial? How was the HER2DX assay assessed?

RESPECT included patients between 70 and 80 years of age with stage I to IIIA HER2-positive breast cancer who had undergone definitive surgery, and patients were randomly assigned to receive adjuvant trastuzumab monotherapy or trastuzumab plus chemotherapy. Those with hormone receptor–positive disease also received adjuvant endocrine therapy.

Tumor samples were analyzed with HER2DX in a central laboratory in Barcelona, Spain; only one sample was profiled per patient, with the sample collected from the primary tumor during resection. The HER2DX assay generated risk and pCR scores stemming from 4 predefined gene expression signatures that encompass 27 genes in order to provide information on immune infiltration, tumor cell proliferation, luminal differentiation, and expression of the HER2 amplicon.

The HER2DX-evaluable population was well balanced between the 2 arms compared with the overall population.

What was found regarding HER2DX pCR scores?

In the HER2DX-evalauble population, 51.3% of patients had pCR-high tumors, 21.4% had pCR-medium tumors, and 27.3% had pCR-low tumors. Notably, HER2DX pCR scores were not significantly associated with RFS or OS outcomes.

The addition of chemotherapy to trastuzumab was found to have a non-significant trend toward improved RFS vs trastuzumab alone in the pCR-high group (HR, 0.44; 95% CI 0.14-1.44); the 10-year RFS rates in the pCR-high subgroup were 88.9% for trastuzumab plus chemotherapy vs 61.4% for trastuzumab alone. Numerically improved outcomes were also reported in the pCR-high subgroup (HR, 0.23; 95% CI, 0.05-1.08), and the 10-year OS rates were 94.4% for chemotherapy plus trastuzumab vs 66.4% for trastuzumab alone.

In the pCR-medium/low subgroups, no benefits were observed with the addition of chemotherapy in terms of RFS (HR, 1.18; 95% CI 0.45-3.10) or OS (HR, 1.68; 95% CI, 0.50-5.60). The 10-year RFS rates in the pCR-medium/low subgroups were 70.6% with trastuzumab plus chemotherapy vs 76.2% with trastuzumab alone; the 10-year OS rates were 76.2% and 88.6%, respectively.

“The HER2DX pCR likelihood score is a genomic predictor developed to estimate the probability of achieving a pCR following neoadjuvant trastuzumab-based chemotherapy in early-stage HER2-positive breast cancer,” study authors explained, noting that the HER2 pCR results should be interpreted with caution due to sample size and the borderline statistical significance. “It reflects tumor-intrinsic features, such as proliferation, luminal, immune infiltration, and HER2 signaling, that are associated with chemosensitivity and response to HER2-targeted agents. In this study, the pCR score identified a subgroup of patients [pCR-high] in which a numerical benefit from chemotherapy was observed. Specifically, patients classified as pCR-high appeared to derive greater benefit from the addition of chemotherapy to trastuzumab, particularly in terms of OS, whereas no such benefit was seen in the pCR-medium/low group.”

ReferencesNozawa K, Sawaki M, Uemura Y, et al. HER2DX in older patients with HER2-positive early breast cancer: extended follow-up from the RESPECT trial of trastuzumab ± chemotherapy. Nat Commun. 2025;16(1):9585. doi:10.1038/s41467-025-65599-xSawaki M, Taira N, Uemura Y, et al. Randomized controlled trial of trastuzumab with or without chemotherapy for HER2-positive early breast cancer in older patients. J Clin Oncol. 2020;38(32):3743-3752. doi:10.1200/JCO.20.00184