Highlights • PIK3CA mutation was significantly associated with lower pCR rate in HER2-positive breast cancer patients treated with neoadjuvant anti-HER2 therapy.• The adverse effect of PIK3CA mutation on pCR remained significant regardless of single- or dual-agent anti-HER2 therapy, and hormone receptor status.• There was no significant association between mutated and wild-type PIK3CA neither in the neoadjuvant setting nor in the adjuvant setting.• In the metastatic setting, PIK3CA mutation was predictive of worse overall response rate, progression-free survival, but not for overall survival. The gene discussed is NR4A1; the disease is breast carcinoma.