Effects of neoadjuvant trastuzumab, pertuzumab and palbociclib on Ki67 in HER2 and ER-positive breast cancer

Luca Gianni,Giancarlo Bisagni,Stefania Zambelli,Lucia Del Mastro,Antonio Frassoldati,Giuseppe Viale,Mauro Mansutti,Marco Colleoni,Giampaolo Bianchini,Ilaria Maffeis,Pinuccia Valagussa,Claudio Zamagni

doi:10.1038/s41523-021-00377-8

Abstract

The crosstalk between estrogen and HER2 receptors and cell-cycle regulation sustains resistance to endocrine therapy of HER2- and hormone receptor-positive breast cancer. We earlier reported that women with HER2 and ER-positive breast cancer receiving neoadjuvant dual HER2-block and palbociclib in the NA-PHER2 trial had Ki67 decrease and 27% pathological complete responses (pCR). We extended NA-PHER2 to Cohort B using dual HER2-block and palbociclib without fulvestrant and report here Ki67 drops at week-2 (mean change −25.7), at surgery (after 16 weeks, mean change −9.5), high objective response (88.5%) and pCR (19.2%). In Cohort C [Ki67 > 20% and HER2low (IHC 1+/2+ without gene amplification)], women also received fulvestrant, had dramatic Ki67 drop at week 2 (−29.5) persisting at surgery (−19.3), and objective responses in 78.3%. In view of the favorable tolerability and of the efficacy-predictive value of Ki67 drop at week-2, the chemotherapy-free approach of NA-PHER2 deserves further investigation in HER2 and ER-positive breast cancer. The trial is registered with ClinicalTrials.gov, number NCT02530424.

Highlights

It has been experimentally established that signaling pathways through the estrogen (ER) and the erbB2 (HER2) receptors converge on CDK1 and eventually to Rb checkpoint regulation[1,2,3]
The positive HER2 status was not confirmed in 6 cases, 2 additional cases had ER status ≤ 10%, mandatory biopsy was unavailable in 4, and one patient received another systemic therapy in the absence of disease progression
The extended study of two additional cohorts of the NA-PHER2 trial showed in cohort B of HER2-amplified breast carcinomas that block of HER2 and cdk4/6 led to a rapid and major drop of Ki67 even without the use of estrogen receptor targeting in spite of estrogen receptor expression

Summary

Introduction

It has been experimentally established that signaling pathways through the estrogen (ER) and the erbB2 (HER2) receptors converge on CDK1 and eventually to Rb checkpoint regulation[1,2,3]. Rb would result in enhanced antitumor activity that is especially attractive in ER+ and HER2+ breast carcinomas. In those so called “triple-positive” tumors neoadjuvant trials consistently showed a lower rate of pathologic complete response (pCR) than in ER negative HER2+ tumors upon exposure to HER2-directed therapies in combination with chemotherapy[4,5,6]. In cohort B we explored the effects of a concomitant block of HER2 and Rb in the absence of fulvestrant in patients with ER-positive and HER2positive (IHC 3+ score or gene amplification by FISH) breast cancers. In cohort C the triple block of HER2, ER and Rb was studied in women with ER+ and HER2low tumors (ICH 1+ or 2+ score and not amplified)

Methods

Results

Conclusion