A phase III study of HR-positive/HER2-negative and lymph node-positive breast cancer non- responsive to primary chemotherapy: a randomized clinical trial

Abstract Background: We evaluated the use of pathological response-guided non-cross-resistant adjuvant chemotherapy in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-)/lymph node-positive (LN+) breast cancer who were non-responsive to primary chemotherapy. Methods: A multi-center, open-label, randomized, controlled phase III trial was conducted. Patients with HR+/HER2−/LN+ breast cancer and non-responsive to four cycles of neoadjuvant chemotherapy (Miller and Payne grade (G) 1 to G3 or any Miller and Payne grade but with residual positive lymph nodes in surgical specimens) were randomly assigned to receive four cycles of non-cross-resistant regimen plus endocrine therapy, or endocrine therapy alone. Patients with Miller and Payne G4 or G5 and LN− status were assigned to the observation group. Distant disease-free survival was the primary endpoint. Results: Of the 433 patients enrolled between October 2010 and September 2018, 391 were non-responsive to treatment, and the final intention-to-treat analysis comprised 379 patients (chemotherapy plus endocrine therapy group, n=187; endocrine therapy-alone group, n=192). Forty patients responsive to neoadjuvant chemotherapy were assigned to the observation group. After a median follow-up period of 72.4 months, the 5-year distant disease-free survival was 92% (95% confidence interval [CI], 88–96%) and 90% (95% CI, 86–94%) in the chemotherapy plus endocrine therapy and endocrine therapy-alone groups, respectively (hazard ratio 0.79, 95% CI 0.45‒1.37; P=0.401). There was no significant difference between any of the prespecified subgroups. Compared to these two randomized groups, the observation group showed a trend towards better distant disease-free survival (P=0.107). Conclusions: For patients non-responsive to neoadjuvant chemotherapy, adjuvant non-cross-resistant chemotherapy did not significantly improve distant disease-free survival compared to endocrine therapy alone. Trial registration: The trial was registered on November 25, 2009, at ClinicalTrials.gov, and the registration number was NCT01019616. https://clinicaltrials.gov/ct2/show/NCT01019616?term=alternative+non-cross-resistant&draw=2&rank=1