Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial

Abstract

Background Preoperative and perioperative aromatase inhibitor (POAI) therapy has the potential to improve outcomes in women with operable oestrogen receptor-positive primary breast cancer. It has also been suggested that tumour Ki67 values after 2 weeks (Ki67 2W ) of POAI predicts individual patient outcome better than baseline Ki67 (Ki67 B ). The POETIC trial aimed to test these two hypotheses. MethodsPOETIC was an open-label, multicentre, parallel-group, randomised, phase 3 trial (done in 130 UK hospitals) in which postmenopausal women aged at least 50 years with WHO performance status 0-1 and hormone receptor-positive, operable breast cancer were randomly assigned (2:1) to POAI (letrozole 2•5 mg per day orally or anastrozole 1 mg per day orally) for 14 days before and following surgery or no POAI (control). Adjuvant treatment was given as per UK standard local practice. Randomisation was done centrally by computer-generated permuted block method (variable block size of six or nine) and was stratified by hospital. Treatment allocation was not masked. The primary endpoint was time to recurrence. A key second objective explored association between Ki67 (dichotomised at 10%) and disease outcomes. The primary analysis for clinical endpoints was by modified intention to treat (excluding patients who withdrew consent). For Ki67 biomarker association and endpoint analysis, the evaluable population included all randomly assigned patients who had paired Ki67 values available. This study is registered with ClinicalTrials.gov, NCT02338310; the European Clinical Trials database, EudraCT2007-003877-21; and the ISRCTN registry, ISRCTN63882543. Recruitment is complete and long-term follow-up is ongoing.

Molecular Biomarkers for Contemporary Therapies in Hormone Receptor-Positive Breast Cancer

“…A pharmacodynamic response in Ki67 to endocrine therapy +/− CDK4/6i was also observed in the Poetic trial, where Ki67 following 2 weeks of therapy improved prediction over baseline Ki67 alone [ 48 , 49 ]. Furthermore, tumours that did not exhibit a Ki67 response following preoperative endocrine therapy were enriched for genomic drivers of endocrine resistance, such as FGFR1 and CCND1 amplification, as well as intrachromosomal ESR1 fusions and enhanced E2F-mediated transcription [ 111 , 112 ].…”

Neoadjuvant Endocrine Therapy in Breast Cancer Management: State of the Art

“…The efficacy threshold of 20% pCR after NCT was not met, since only two of the 35 patients included in the trial achieved a pCR [ 52 ], showing the disappointing efficacy of NCT in patients with “primary resistance” to NET. The phase III POETIC trial randomized 2:1 postmenopausal ER+ BC patients to receive 2 weeks preoperative and postoperative AI vs. no perioperative treatment [ 59 ]. The primary endpoint was time to recurrence (TTR) and the secondary endpoint was Ki67 at baseline and after 2 weeks of AI as predictor of outcome.…”

Treatment of Patients with Early Breast Cancer: Evidence, Controversies, Consensus

“…They also voted by a majority (70 %) that the prognosis of patients with ER+/HER2− ductal breast cancer can be assessed by the change in Ki-67 levels after a 2-week course of endocrine therapy (NET). The German experts agree that a 2-4 week NET to assess endocrine sensitivity, as used for example in the German ADAPT trial [8] and in the POETIC trial [9], is an appropriate measure [1].…”