Mutation in the ShortHER Randomized Adjuvant Trial for Patients with Early HER2 Breast Cancer: Association with Prognosis and Integration with PAM50 Subtype.

Purpose: We explored the prognostic effect of mutation in HER2 patients enrolled in the ShortHER trial.

Patients And Methods: The ShortHER trial randomized 1,253 patients with HER2 breast cancer to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. hotspot mutations in exon 9 and 20 were analyzed by pyrosequencing. Expression of 60 genes, including PAM50 genes was measured using the nCounter platform.

Results: A mutation of the gene was detected in 21.7% of the 803 genotyped tumors. At a median follow-up of 7.7 years, 5-year disease-free survival (DFS) rates were 90.6% for mutated and 86.2% for wild-type tumors [HR, 0.84; 95% confidence interval (CI), 0.56-1.27; = 0.417]. mutation showed a favorable prognostic impact in the PAM50 HER2-enriched subtype ( = 232): 5-year DFS 91.8% versus 76.1% (log-rank = 0.049; HR, 0.46; 95% CI, 0.21-1.02). HER2-enriched/ mutated versus wild-type tumors showed numerically higher tumor-infiltrating lymphocytes (TIL) and significant upregulation of immune-related genes (including and , a proliferation gene involved in immune processes). High TILs as well as the upregulation of and were associated with a significant DFS improvement within the HER2-enriched subtype (HR, 0.82; 95% CI, 0.68-0.99; = 0.039 for 10% TILs increment; HR, 0.81; 95% CI, 0.65-0.99; = 0.049 for expression; HR, 0.72; 95% CI, 0.53-0.99; = 0.042 for expression).

Conclusions: mutation showed no prognostic impact in the ShortHER trial. Within the HER2-enriched molecular subtype, patients with mutated tumors showed better DFS versus wild-type, which may be partly explained by upregulation of immune-related genes.