PIK3CA 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 PIK3CA mutation in HER2-positive patients enrolled in the ShortHER trial. Experimental Design: The ShortHER trial randomized 1253 patients with HER2-positive breast cancer to 9-weeks or 1-year of adjuvant trastuzumab combined with chemotherapy. PIK3CA hot-spot mutations in exon 9 and 20 were analysed by Pyrosequencing. Expression of 60 genes, including PAM50 genes was measured using the nCounter platform. Results: A mutation of the PIK3CA gene was detected in 21.7% of the 803 genotyped tumors. At a median follow up of 7.7 years, 5-yr disease-free survival (DFS) rates were 90.6% for PIK3CA mutated and 86.2% for PIK3CA wild-type tumors (HR 0.84, 95%CI 0.56-1.27, P=0.417). PIK3CA mutation showed a favorable prognostic impact in the PAM50 HER2-enriched subtype (n=232): 5-yr DFS 91.8% vs 76.1% (log-rank P=0.049; HR 0.46 95%CI 0.21-1.02). HER2-enriched/ PIK3CA mutated vs wild-type tumors showed numerically higher tumor infiltrating lymphocytes (TILs) and significant upregulation of immune-related genes (including CD8A, CD274, PDCD1 and MYBL2, a proliferation gene involved in immune processes). High TILs as well as the upregulation of PDCD1 and MYBL2 were associated with a significant DFS improvement within the HER2-enriched subtype (HR 0.82, 95%CI 0.68-0.99, P=0.039 for 10% TILs increment; HR 0.81, 95%CI 0.65-0.99, P=0.049 for PDCD1 expression; HR 0.72, 95%CI 0.53-0.99, P=0.042 for MYBL2 expression). Conclusions: PIK3CA mutation showed no prognostic impact in the ShortHER trial. Within the HER2-enriched molecular subtype, patients with PIK3CA mutated tumors showed better DFS vs PIK3CA wild-type that may be partly explained by upregulation of immune-related genes.