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Updated: Jan 9, 2026
Optimization of a Multiplex RNA-based Expression Assay Using Breast Cancer Archival Material
Published on: August 1, 2018
Spatial molecular analyses reveal key features associated with response to KN026 in advanced HER2-positive breast
Jianli Ma1, Shengnan Sun2, Xiaowen Tang3
1Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, PR China.
Background:
KN026 is a novel bispecific HER2-targeting antibody for HER2-positive recurrent or metastatic breast cancer that showed prolonged median PFS and lessened distinction of PFS regarding the HR subgroup in our phase II clinical trial, compared with PUFFIN study of first-line trastuzumab combined with pertuzumab therapy. A more detailed discovery of its peculiarity is needed for optimal application of KN026 treatment.
Methods:
We performed whole-transcriptome sequencing of digital spatial profiling (DSP) on 8 pre/post-treatment tumor samples. Mechanistic explorations were conducted by plasmid transfection, co-culture, CCK8 proliferation assay and flow cytometry.
Results:
Compared to the tumor regions with non-objective response (OR), those with OR had high expression of CALML5, TFAP2B, and ERBB2, and relatively low expression of ESR1 in tumor cells at baseline. The expression of ESR1 had a tentative association with PI3K/AKT and NOTCH signaling pathways which were downstream or interactive pathways of HER2 target and also acted as interactive pathways of ER-mediated signaling. The co-expression of ERBB2 and CDK12 emerged as a distinctive signature of OR. KN026 treatment also reshaped intratumoral activated T- and B-cell subtypes in hot-tumor regions, regardless of myeloid-derived cells.
Conclusions:
Both HER2 and ESR1 are determinant of KN026 efficacy in advanced HER2-positive breast cancer, implying the potential of KN026 combined with endocrine therapy in HER2- and ER-positive breast cancer.
Insights
KN026, a bispecific HER2 antibody, shows efficacy in advanced HER2-positive breast cancer. Its effectiveness is linked to HER2 and estrogen receptor (ESR1) expression, suggesting potential combination with endocrine therapy.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- KN026 is a novel bispecific HER2-targeting antibody for HER2-positive recurrent or metastatic breast cancer.
- Phase II trials show KN026 offers prolonged progression-free survival (PFS) compared to trastuzumab plus pertuzumab.
- Further investigation is needed to understand KN026's unique mechanisms for optimal treatment application.
Purpose of the Study:
- To explore the molecular mechanisms underlying KN026 efficacy in HER2-positive breast cancer.
- To identify predictive biomarkers for KN026 response.
- To investigate the impact of KN026 on the tumor microenvironment.
Main Methods:
- Whole-transcriptome sequencing of digital spatial profiling (DSP) on pre/post-treatment tumor samples.
- Mechanistic studies including plasmid transfection, co-culture, CCK8 proliferation assay, and flow cytometry.
Main Results:
- Objective response (OR) to KN026 was associated with high baseline expression of CALML5, TFAP2B, and ERBB2, and low ESR1 in tumor cells.
- ESR1 expression showed associations with PI3K/AKT and NOTCH signaling pathways, downstream or interactive with HER2 and ER signaling.
- Co-expression of ERBB2 and CDK12 was a distinctive signature of OR. KN026 modulated intratumoral T- and B-cell subtypes.
Conclusions:
- Both HER2 and ESR1 expression levels are critical determinants of KN026 efficacy in advanced HER2-positive breast cancer.
- KN026 demonstrates potential for combination with endocrine therapy in HER2- and ER-positive breast cancer.
- Understanding these biomarkers can guide personalized treatment strategies for breast cancer patients.
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