Incidence and prognostic impact of HER2‐positivity loss after dual HER2‐directed neoadjuvant therapy for HER2+ breast cancer

Abstract

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.

Invasive Disease Free Survival and Brain Metastasis Rates in Patients Treated with Neoadjuvant Chemotherapy with Trastuzumab and Pertuzumab

“…There have been mixed results regarding the prognosis of patients who have HER2(-) RD, with older retrospective studies showing a higher risk of relapse compared to those who have HER2(+) RD [18,19]. However, more recent data with modern patient cohorts do not show inferior oncologic outcomes for patients who have HER2(-) RD, which is also re ected in our current ndings [15,20]. A subset analysis of the KATHERINE trial suggests that patients with HER2(-) RD (8%) have better IDFS with adjuvant T-DM1 versus trastuzumab alone and suggests that adjuvant T-DM1 should be offered in this patient population [7].…”

“…It is well established that patients with HER2(+) EBC receiving NAST have poorer outcomes if they have RD after surgery which is mirrored in our ndings [13]. Loss of HER2 positivity in RD after NAST has been reported in literature to occur in 20-40% of patients [14][15]. Theories regarding the mechanism behind HER2 loss include the effect of breast cancer heterogeneity, where HER2(+) subpopulations are killed by treatment which leads to the selected survival of resistant HER2(-) cells [16].…”