Clinical implications of HER2 mRNA expression and intrinsic subtype in refractory HER2-positive metastatic breast cancer treated with pan-HER inhibitor, poziotinib.

Introduction: We explored clinical implication of intrinsic molecular subtype in human epidermal growth factor receptor 2 (HER2) + metastatic breast cancer (BC) with pan-HER inhibitor from a phase II clinical trial of poziotinib in refractory HER2+BC patients.

Methods: For this translational research correlated with phase II clinical trial, we performed an nCounter expression assay, using gene panel including 50 genes for PAM50 prediction and targeted deep sequencing.

Results: From 106 participants, we obtained 97 tumor tissues and analyzed gene expression in 91 of these samples. Of 91 HER2+BCs, 40 (44.0%) were HER2-enriched (E) intrinsic molecular subtype, 17 (18.7%) of Luminal A, 16 (17.6%) of Basal-like, 14 (15.4%) of Luminal B and 4 (4.4%) of Normal-like. HER2-E subtype was associated with hormone receptor negativity (odds ratio [OR] 2.93; p = 0.019), 3 + of HER2 immunohistochemistry(IHC) (OR 5.64; p = 0.001), high mRNA expression of HER2 (OR 14.43; p = 0.001) and copy number(CN) amplification of HER2 (OR 12.80; p = 0.005). In genetic alterations, alteration was more frequently observed in HER2-E subtype (OR 3.84; p = 0.022) but there was no association between PIK3CA alteration and HER2-E subtype (p = 0.655). In terms of drug efficacy, high mRNA expression of HER2 was the most powerful predictor of poziotinib response (median progression-free survival [PFS): 4.63 months [high] vs. 2.56 [low]; p < .001). In a combination prediction model, median PFS of intrinsic subtypes except Her2-E with high HER2 mRNA expression without PIK3CA genetic alteration was 6.83 months and that of the remaining group was 1.74 months (p < .001).

Conclusion: HER2-E subtype was associated with hormone receptor status, HER2 IHC, CN and mRNA expression and TP53 mutation. In survival analysis, the information of level of HER2 mRNA expression, intrinsic molecular subtype and PI3K pathway alteration would be independent predictors to poziotinib treatment. ClinicalTrials.gov identifier: NCT02418689.