Abstract P4-21-39: Neo-adjuvant treatment with trastuzumab and pertuzumab associated with palbociclib and fulvestrant in HER2-positive and ER-positive breast cancer: Effect on Ki67 during and after treatment. A phase II Michelangelo study
Authors: Gianni L , Bisagni G , Colleoni M , Del Mastro L , Zamagni C , Mansutti M , Zambetti M , Frassoldati A , De Fato R , Valagussa P , Viale G 
Published: March 2017

Abstract
Background: In metastatic breast cancer, the CDK4,6 inhibitor palbociclib associated with fulvestrant proved superior to fulvestrant alone in HER2-negative breast cancer (NEJM 2015). In HER2-positive tumors, the dual blockade of the receptor plus an aromatase inhibitor led to a 21% rate of pCR in a neoadjuvant setting in ER+ cancers (J Clin Oncol 2013). In preclinical studies concomitant inhibition of CDK4,6 and trastuzumab led to synergistic antitumor activity (Cancer Cell 2016). The extent of early change and the persistence of Ki67 down-regulation are robust markers of the effects of endocrine treatments in hormone receptors positive breast carcinomas in the setting of neoadjuvant endocrine therapy (Ann Oncol 2012).
Methods: In this exploratory Phase II trial (NCT02530424), women with invasive unilateral non metastatic ER-positive breast cancer expressing HER2 and suitable for neoadjuvant therapy were treated with every 3 wks trastuzumab and pertuzumab for 6 cycles combined with palbociclib 125 mg po q.d. x 21 q. 4 wks and fulvestrant i.m. 500 mg, both given for 5 cycles (HPPF). The primary endpoint was characterization of Ki67 changes from baseline before therapy, at 2 weeks and at surgery.
Results: A total of 23 patients with centrally confirmed HER2 and ER positive breast cancer were recruited for this study. Ki67 was also assessed centrally. At baseline 30% of cases were classified as locally advanced, 43% as cN0 and 78% had Ki67 values &gt; 20%. Objective clinical response was documented in 96% of patients and pCR (absence of invasive cells in breast and axillary nodes) was documented in 22% (pCR in breast only was 26%). The geometric means of Ki67 expression assessed at baseline, after 2 weeks of treatment and at surgery were 30.8 (SD 15.1), 3.9 (SD 15.9) and 9.2 (SD 16.6) respectively. The mean change in Ki67 values from baseline to after 2 weeks was -24.5 (paired t-test: P &lt; 0.0001) and -13.9 (P = 0.008) from baseline to surgery. Treatment was fairly well tolerated. No serious adverse events &gt; grade 3 were reported. The most frequent G 3 adverse events were neutropenia (26% of patients) and gastrointestinal disorders (17%).
Conclusions: Neoadjuvant triple targeting of ER, HER2 and Rb in HER2+/ER+ breast cancer treatment caused a significant and rapid decrease of Ki67 that was of larger magnitude after 2 weeks than at surgery irrespective of the recorded objective clinical response. The good tolerability, the rapid effect on Ki67, the consistent clinical response, and the rate of pCR with this chemotherapy-free approach support further clinical testing and additional molecular characterization.
Supported in part by an unrestricted grant from Pfizer Italia S.r.l. and from Roche S.p.a. Italia
Citation Format: Gianni L, Bisagni G, Colleoni M, Del Mastro L, Zamagni C, Mansutti M, Zambetti M, Frassoldati A, De Fato R, Valagussa P, Viale G. Neo-adjuvant treatment with trastuzumab and pertuzumab associated with palbociclib and fulvestrant in HER2-positive and ER-positive breast cancer: Effect on Ki67 during and after treatment. A phase II Michelangelo study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-39.