Neoadjuvant endocrine therapy with sequential palbociclib and chemotherapy based on Ki67 status in stage II-III breast cancer: An open-label, phase II study.

BACKGROUND: While neoadjuvant endocrine therapy (NET), with or without a CDK4/6 inhibitor, is an established treatment option for estrogen receptor-positive breast cancers, optimal patient selection and second-line treatment for non-responders remain uncertain.

METHODS: In the open-label, phase 2 PETREMAC trial (NCT02624973), pre- and postmenopausal patients with large T2 (>4 cm) or locally advanced ER/PGR>50 %, HER2-, and TP53 wild-type breast cancers received NET (tamoxifen + goserelin for premenopausal and letrozole for postmenopausal patients). Palbociclib was added if the Ki67 reduction was ≤50 % after 14 days. Neoadjuvant chemotherapy (NAC) was introduced if NET ± palbociclib failed to reduce Ki67 sufficiently or if there was no objective response on MRI after 24 weeks. Tumor biopsies underwent targeted sequencing of 360 cancer-related genes and subsequent gene expression profiling.

RESULTS: Among 88 patients, the median tumor size was 48 mm (range 16-140 mm). NET alone reduced Ki67 > 50 % in 49/88 (56 %) of evaluable tumors. Adding palbociclib yielded a Ki67 reduction >50 % in 24/34 (71 %) of tumors where neoadjuvant endocrine therapy alone failed to suppress Ki67, providing a Ki67 reduction of >50 % in a total of 72/88 (82 %) of patients. NAC was administered to 34/88 (39 %) due to inadequate Ki67 response or lack of MRI response. Overall, 70 % achieved a pre-surgical objective response. Pathological complete response was seen in 3/84 patients. Postmenopausal status (p = 0.005) and invasive lobular carcinoma (p = 0.02) predicted Ki67-based response to NET.

CONCLUSION: Sequential NET with palbociclib, limiting NAC to non-responders, is a feasible strategy for ER/PGR>50 %, HER2-, TP53 wild-type breast cancers.