Prediction of survival after de-escalated neoadjuvant therapy in HER2-positive early breast cancer: a pooled analysis of three WSG trials

BACKGROUND: We analyzed outcomes and survival predictors in three West German Study Group (WSG) randomized de-escalation trials (ADAPT-HR-/HER2+, ADAPT-TP, TP-II) in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (eBC) investigating short (12-week) neoadjuvant treatments with or without chemotherapy. PATIENTS AND METHODS: A total of 713 patients were analyzed; neoadjuvant chemotherapy (paclitaxel plus pertuzumab plus trastuzumab): n = 149, neoadjuvant chemotherapy-free (pertuzumab plus trastuzumab, trastuzumab-only)/antibody-drug conjugate (ADC, trastuzumab emtansine) treatment: n = 564. Patients with pathological complete response (pCR, ypT0/is ypN0) were allowed to omit further chemotherapy; chemotherapy was mandatory after non-pCR. The primary endpoint of each trial was pCR; survival was the secondary endpoint. Survival was analyzed using the Kaplan-Meier method and Cox regression. RESULTS: Median follow-up was 60.7 months. In total, 10 (7%) and 74 (13%) invasive disease-free survival (iDFS) events, 8 (5%) and 51 (9%) distant DFS (dDFS) events, and 6 (4%) and 34 (6%) deaths occurred in the neoadjuvant chemotherapy and chemotherapy-free/ADC groups, respectively; the respective 5-year survival rates were 96% [95% confidence interval (CI) 92% to 99%] and 88% (95% CI 85% to 91%) for iDFS (hazard ratio 0.56, 95% CI 0.29-1.08, P = 0.083) and 98% (95% CI 93% to 99%) and 97% (95% CI 95% to 98%) for overall survival (hazard ratio 0.88, 95% CI 0.36-2.11, P = 0.775). The 5-year iDFS rates in patients with pCR were 98% (95% CI 91% to 99%) after chemotherapy and 94% (95% CI 89% to 97%) after chemotherapy-free/ADC treatment (hazard ratio 0.76, 95% CI 0.27-2.12, P = 0.609). iDFS was comparable between patients with and without adjuvant chemotherapy after pCR to chemotherapy-free/ADC treatment (hazard ratio 1.25, 95% CI 0.39-4.00, P = 0.712). In multivariable analysis, node-negative status and pCR were favorably associated with iDFS in the chemotherapy-free/ADC group. CONCLUSIONS: This pooled analysis demonstrates that neoadjuvant de-escalation trials with further pCR-adapted treatment (de-)escalation are feasible and appear safe for HER2-positive eBC patients. Twelve-weekly neoadjuvant paclitaxel plus HER2 blockade is effective and well tolerated. Neoadjuvant chemotherapy-free/ADC treatments can be viable alternatives for stage I-II eBC. Excellent survival after pCR to neoadjuvant chemotherapy-free/ADC treatment lays the groundwork for further de-escalation strategies.