Charles Edward Geyer, MD Houston Methodist discusses the ASCO 2020 abstract entitled Biomarker data from KATHERINE: A phase III study of adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab (H) in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer
The KATHERINE Phase 3 analysis (NCT01772472) compared adjuvant T-DM1 versus H after neoadjuvant chemotherapy in patients with residual invasive breast cancer plus HER2-targeted therapy. Here we disclose exploratory analysis of the relationship between invasive disease-free survival (IDFS) and potentially reaction-related biomarkers.
Samples of fixed paraffin-embedded tissue were obtained before and/or in the course of neoadjuvant therapy. Surgical samples were used for analysis, even when only samples were available for pretreatment (~20 percent of cases). DNA was extracted to recognize PIK3CA hotspot mutations and gene expression (RNA) analysis to detect signatures of HER2, PD-L1, CD8 and predefined immune signatures including 3-gene, 5-gene, Teffector, chemokine signaling, and checkpoint inhibitors. Analysis of RNA was balanced for tumor content and the level of expression was dichotomized in low (almost) and high (>) groups at the median level. Treatment and biomarker effects were measured on IDFS.
The status of PIK3CA mutation (mut) was available from 1363 patients (91.7 per cent). T-DM1 IDFS benefit was independent of the mutual status of PIK3CA (mut: HR 0.54; 95 per cent CI 0.23–0.90; non-mut: HR 0.48; 95 per cent CI 0.35–0.65) and no impact of PIK3CA mut was observed within either arm. Data on gene expression were available in 1059 patients (71.3 per cent). Similar levels of gene expression were observed between treatment arms, but unlike surgical samples (n = 815), the pretreatment samples (n = 244) were not representative of the ITT population. Subsequent analyzes were therefore focused upon surgical samples (H n = 398; T-DM1 n = 417). In the single-gene and immune-gene-signature subgroups as in the ITT population, clear treatment gain with T-DM1 vs H has been observed. High vs low expression of HER2 was correlated with worse outcome (HR 2.02; 95 % CI 1.32–3.11) within the H arm but not within the T-DM1 arm (HR 1.01; 95% CI 0.56–1.83). High vs low PD-L1 expression was correlated with better outcome within the H arm (HR 0.66; 95 % CI 0.44–1.00) but not within the T-DM1 arm (HR 1.05; 95 % CI 0.59–1.87); Similar patterns were found in the subgroups of checkpoint inhibitors.
These exploratory analyzes provide the first evidence on the relationship between expression of biomarkers in residual disease, following HER2-targeted therapy and performance. PIK3CA mut status had no effect on outcomes with either H or T-DM1. The T-DM1 gain seemed to be independent of all measured biomarkers. Information regarding clinical trials: NCT01772472.