Background Loss of HER2 “positivity” can occur in patients with residual disease after neoadjuvant treatment, but the incidence of HER2‐positivity loss after neoadjuvant dual HER2‐targeted treatment plus chemotherapy, the current standard‐of‐care for most early stage HER2‐positive breast cancers, is not well described. Previous studies that report the HER2 discordance rate after neoadjuvant treatment also do not include the novel HER2‐low category. In this retrospective study, we determine the incidence and prognostic impact of HER2‐positivity loss, including the evolution to HER2‐low disease, after neoadjuvant dual HER2‐targeted therapy with chemotherapy. Methods Clinicopathologic data for patients with stage I‐III HER2+ breast cancer diagnosed between 2015 and 2019 were reviewed in this single institution retrospective study. Patients who received dual HER2‐targeted treatment with chemotherapy were included, and HER2 status before and after neoadjuvant therapy was interrogated. Results A total of 163 female patients were included in the analysis with a median age of 50 years. A pathologic complete response (pCR as defined by ypT0/is) was achieved in 102 (62.5%) of 163 evaluable patients. Among the 61 patients with residual disease after neoadjuvant therapy, 36 (59.0%) had HER2‐positive and 25 (41.0%) had HER2‐negative residual disease. Of the 25 patients with HER2‐negative residual disease, 22 (88%) of patients were classified as HER2‐low. After a median follow‐up of 3.3 years, patients who retained HER2‐positivity after neoadjuvant treatment had a 3‐year IDFS rate of 91% (95% CI, 91%–100%), while patients who lost HER2‐positivity had a 3‐year IDFS rate of 82% (95% CI, 67%–100%). Conclusion Almost half of patients with residual disease following neoadjuvant dual HER2‐targeted therapy plus chemotherapy lost HER2‐positivity. The loss of HER2‐positivity may not confer negative prognostic impact, although the results were limited by short follow‐up time. Further research on the HER2 status after neoadjuvant treatment may help guide treatment decisions in the adjuvant setting.

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