Comprehensive Assessment of Immune Phenotype and Its Effects on Survival Outcomes in HER2-Low versus HER2-Zero Breast Cancer.

Background: The understanding of molecular characteristics of HER2-low breast cancer is evolving since the establishment of trastuzumab deruxtecan. Here, we explore the differences in expression patterns of immune-related genes in the tumor immune microenvironment (TME) and survival between HER2-low and HER2-zero breast cancers.
Methods: Comprehensive genomic and immune profiling, including RNA-seq gene expression assessment of 395 immune genes, was performed on FFPE samples from 129 patients with advanced HER2-negative (immunohistochemistry (IHC) 0, 1+ or 2+ with negative ERBB2 amplification by in-situ hybridization) breast cancer. Both estrogen receptor (ER) and HER2 statuses were obtained from available pathology reports. mRNA expressions of immune biomarkers, except for PD-L1 IHC and TMB, were derived from RNA-seq. Statistical comparisons were performed using the Kruskal-Wallis or Wilcoxon Rank-Sum test or the two-sample test for equality of proportions with continuity correction (p≤0.05 for significance). Survival differences were calculated using Kaplan-Meier analysis (p≤0.05 for significance).
Results: There were no significant differences in mRNA expressions of immune-related genes between HER2-low and HER2-zero breast cancers. However, HER2-low breast cancers were associated with a higher proportion of ER-positivity. When ER was analyzed along with HER2, we observed a significantly higher tumor immunogenic signature (TIGS) expression in HER2-zero/ER-negative tumors than in HER2-low/ER-positive tumors (p=0.0088). Similarly, lower expression of PD-L1 and T cell immunoglobulin and ITIM domain (TIGIT) mRNA was observed in HER2-low/ER-positive tumors when compared to HER2-zero/ER-negative tumors (p=0.014 and 0.012, respectively). Patients with HER2-low tumors had a longer median OS than those with HER2-zero tumors (94 months vs 42 months, p=0.0044).
Conclusion: Patients with HER2-low breast cancer have longer survivals yet display no differences in immune-related gene expression when compared to those with HER2-zero cancers. The differences in survival can be attributed to the higher rate of ER-positivity seen in HER2-low breast cancers, compared to HER2-zero tumors.
Competing Interests: HCK, RJS, SP, MFS, EVR, SG, KCS, RAP, MFG, MC, MKN, SBH, KAA, SZ, JMC, TJJ, ME, BC, EAS, and SR are employees of Labcorp Oncology, a business unit of Labcorp. SG is an employee at Roswell Park Comprehensive Cancer Center. ME and BJC are employees of Labcorp. RJS, EVR, SG, SP, and JMC are listed as authors on a pending patent US2022/049867 entitled Methods and Systems for Analyzing and Utilizing Cancer Testis Antigen Burden. JC and SP report a pending patent US20220136070A1 Methods and Systems for Characterizing Tumor Response to Immunotherapy Using an Immunogenic Profile pending to OmniSeq, Inc. SP reports patents US11427873B2 Methods and systems for assessing proliferative potential and resistance to immune checkpoint blockade and US11515008B2 Methods and systems of prioritizing treatments, vaccination, testing and/or activities while protecting the privacy of individuals issued to Omniseq. TJJ, EAS, MKN, KCS are shareholder of Labcorp. TJJ is a shareholder in Fortrea. The authors report no other conflicts of interest in this work.
(© 2024 Ko et al.)