What question did this study set out to answer?

To evaluate the role of germline mutations in breast cancer patients with varying HER2 expression levels.

February 19, 2026

Abstract PS3-05-21: Pathogenic germline variants associated with different HER2 expression among breast cancer patients

Q: What does this research mean for the field?

Breast cancer patients with different HER2 expression statuses harbor distinct pathogenic germline variant signatures that correlate with differential clinical outcomes following neoadjuvant systemic therapy. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.CHALLENGES_CONSENSUS.

Key Points

To evaluate the role of germline mutations in breast cancer patients with varying HER2 expression levels.
Analyzed germline mutations in 530 breast cancer patients and 98 individuals with atypical ductal hyperplasia or family history.
Utilized next-generation sequencing on a multigene panel targeting 102 cancer-associated genes.
Assessed the correlation between identified variants and clinicopathologic characteristics.
Identified 71 pathogenic variants categorized into five pathway clusters.
Distinct variant distributions were observed between breast cancer patients and unaffected individuals, with significant differences in the BRCA/FANC and DDR clusters.
The HER2-low and HER2-zero groups displayed unique pathogenic variant distributions, notably differing from those in HER2-high patients.

Abstract

Abstract Purpose: Germline mutations were evaluated in 530 Chinese breast cancer (BC)patients with different HER2 expression status plus 98 patients with atypical ductalhyperplasia or a breast cancer family history. Methods: DNA extracted from blood samples was analyzed with a next generationsequencing based multigene panel, with reporting of likely pathogenic and pathogenicvariants (PV) of 102 cancer associated genes, and correlation betweenclinicopathologic characteristics and known BC-associated genes. Results: The 71 identified PVs were categorized into five distinct pathway clusters:BRCA/FANC, DDR, HRR, FANC, and Other. The distribution of PVs enriched withinthese clusters differed significantly between BC patients and unaffected individuals(p=0.031). This difference was primarily driven by the BRCA/FANC, FANC, and DDRclusters, with enrichment percentages of 57.7% vs. 16.7% (BRCA/FANC), 7.0% vs.25.0% (FANC), and 15.5% vs. 41.7% (DDR) in BC vs. unaffected groups, respectively.Notably, the three BC groups stratified by HER2 expression level exhibited distinct PVdistributions. Both the HER2-low and HER2-zero BC groups showed significantlydifferent distributions compared to unaffected individuals (p=0.0132 and p=0.0081,respectively). The BRCA/FANC cluster was the predominant pathway enriched in bothHER2-low (59.6%) and HER2-zero (81.8%) groups. Furthermore, the PV distributionin the HER2-zero group was significantly different from that in the HER2-high group(p=0.0028). In contrast, the distribution in the HER2-high group resembled thatobserved in non-BC individuals. These findings indicate that BC patients with differentHER2 expression statuses harbor distinct germline PV signatures, which correlate withdifferential clinical outcomes following neoadjuvant systemic therapy. Discussion: Chinese breast cancer patients with different HER2 expression statusdemonstrated different pathogenic germline variant, which correlated with differentclinical outcome after neoadjuvant therapy. Multi-gene genetic test for pathogenicgermline variant should be offered to breast cancer patients as well as high-riskindividuals at risk for future breast cancer who would benefit from prevention and earlydetection programs. Citation Format: N. Liao, J. Wu, G. Zhang, J. Weitzel, C. Balch. Pathogenic germline variants associated with different HER2 expression among breast cancer patients abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-05-21.

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