Precision de-escalation in HER2-enriched breast cancer: promise and pitfalls of multiomic response predictors
Year: 2026
Type: article
Abstract: The management of human epidermal growth factor receptor 2-positive (HER2positive) early breast cancer (eBC) is increasingly being reframed from uniform treatment intensification toward biomarker-guided de-escalation.Contemporary neoadjuvant regimens combining dual anti-HER2 blockade with multi-agent chemotherapy achieve high pathologic complete response (pCR) rates, and pCR has been associated with improved event-free survival (EFS) and overall survival (OS) in HER2-positive disease (1).However, these benefits are counterbalanced by acute and long-term toxicities, impaired health-related quality of life, and increased healthcare resource utilization.Therefore, chemotherapy de-escalation can only be considered clinically acceptable when patients with high sensitivity to targeted therapy are identified with sufficient predictive accuracy (2).The parent West German Study Group (WSG)-Keyriched-1 study must be interpreted with caution (3).Although the observed pCR rate was clinically provocative, the trial did not meet its prespecified statistical criterion for success.In the full analysis set, centrally assessed pCR was observed in 20 of 43 patients (47%), with a lower bound of the one-sided 95% CI of 33%; therefore, the null hypothesis that the pCR rate did not exceed 40% could not be rejected.Consequently, subsequent biomarker-defined analyses from this trial should not be viewed as confirmatory evidence, but rather as exploratory analyses intended to generate hypotheses for prospective validation.Against this methodological background, Graeser et al. reported a multiomic factor analysis within the phase II WSG-Keyriched-1 trial (3).This study evaluated a 12week chemotherapy-free neoadjuvant regimen comprising pembrolizumab combined with dual HER2 blockade with trastuzumab and pertuzumab in patients with HER2-enriched eBC.The investigators reported a candidate multiomic responseassociated factor generated through a complex testing strategy that integrated baseline gene expression, including FNBP1, CD36, MYCN, and SIX1, ribonucleic acid (RNA)-based profiling with the breast cancer 360 gene expression panel (BC360) panel, spatial distribution of stromal immune markers assessed by multiplexed https://tbcr.amegroups.
Institution: Instituto Nacional de Câncer - INCA
Language: English
Topic: HER2/EGFR in Cancer Research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W7223129638