Ki-67 response-guided preoperative chemotherapy for HER2-positive breast cancer: results of a randomised Phase 2 study

Hirofumi Mukai,Takeshi Yamaguchi,Tsutomu Takashima,Yasuaki Sagara,Satoshi Yamashita,Tomomi Fujisawa,Tatsuya Toyama,Satoshi Fujii,Yasuo Hozumi,Youngjin Park,Reiki Nishimura,Hiromitsu Akabane,Shigeru Imoto,Shozo Ohsumi,Yukari Uemura,Toshiro Mizuno,Masato Takahashi

doi:10.1038/s41416-020-0815-9

Abstract

BackgroundThe effectiveness of a therapeutic strategy that switches chemotherapy, based on Ki-67 tumour expression after initial therapy, relative to that of standard chemotherapy, has not been evaluated.MethodsPatients were randomly assigned to the control arm or the Ki-67 response-guided arm (Ki-67 arm). Primary tumour biopsies were obtained before treatment, and after three once-weekly doses of paclitaxel and trastuzumab to assess the interim Ki-67 index. In the control arm, paclitaxel and trastuzumab were continued for a total of 12 doses, regardless of the interim Ki-67 index. In the Ki-67 arm, subsequent treatment was based on the interim Ki-67 index. Ki-67 early responder is defined as the absolute Ki-67 value that was <10%, and the percentage of Ki-67-positive tumour cells was reduced by >30% compared with before treatment. Early Ki-67 responders continued to receive the same treatment, while early Ki-67 non-responders were switched to epirubicin plus cyclophosphamide. The primary endpoint was the pathological complete response (pCR) rate.ResultsA total of 237 patients were randomised. There was almost linear correlation between the Ki-67 reduction rate at interim assessment and the pCR rate. The pCR rate in Ki-67 early non-responders in the Ki-67 arm was inferior to that in the control arm (44.1%; 31.4–56.7; P = 0.025).ConclusionsThe standard chemotherapy protocol remains as the recommended strategy for patients with HER2-positive breast cancer.Clinical trial registrationClinical Trial Registration: UMIN-CTR as UMIN000007074.

Highlights

The effectiveness of a therapeutic strategy that switches chemotherapy, based on Ki-67 tumour expression after initial therapy, relative to that of standard chemotherapy, has not been evaluated
Studies suggest that a high pathological complete response rate may be achieved by incorporating trastuzumab into preoperative chemotherapy,[4,5] novel therapeutic strategies are required to increase the pCR rate
Preoperative and postoperative chemotherapy regimens are almost entirely predetermined by clinical evidence and expert consensus based on the risk factors of recurrence and subtype of breast cancer.[6]

Summary

BACKGROUND

Estimates suggest that HER2-positive breast cancer accounts for 15–20% of all breast cancer cases, and HER2 is an independent prognostic factor.[1]. Accurate assessment of therapeutic responses using a biological marker would enable continuous administration of chemotherapy regimens with poor efficacy to be stopped, and the introduction of different drugs with potentially higher efficacy at an earlier stage. This strategy is considered to be of great relevance in the context of precision medicine. 1234567890();,: Ki-67 early responder (n = 20) continue weekly PTX + T pCR 40.0% The aim of this prospective, Phase 2 study was to compare the effectiveness of drug switching, using the Ki-67 index as a biological marker of early responses, with that of the conventional strategy of a continuous pre-specified chemotherapy regimen. Cancer biopsies were obtained during treatment to analyse the biological response

METHODS

RESULTS

DISCUSSION