Tumor biomarkers and efficacy in patients treated with trastuzumab emtansine + pertuzumab versus standard of care in HER2-positive early breast cancer: an open-label, phase III study (KRISTINE)

Breast Cancer Research

Research

Michael F. Press¹  Gail D. Lewis²  Sara A. Hurvitz³  Dennis J. Slamon⁴  Miguel Martin⁵  Sanne L. de Haas⁶  Chiara Lambertini⁶  Vanesa Lopez-Valverde⁷  Thomas Boulet⁸  Aleix Prat⁹ 

[1] Department of Pathology, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA;Discovery Oncology, Genentech, Inc., South San Francisco, CA, USA;Division of Hematology-Oncology, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA;Division of Hematology/Oncology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA;Medical Oncology Service, Hospital Gregorio Marañón, Universidad Complutense, CIBERONC, Madrid, Spain;Oncology Biomarker Development, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland;Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland;Product Development Biometrics Biostatistics, F. Hoffmann-La Roche Ltd., Basel, Switzerland;Translational Genomics and Targeted Therapies in Solid Tumors, IDIBAPS, Barcelona, Spain;Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain;Department of Medicine, University of Barcelona, Barcelona, Spain;

关键词: Tumor biomarkers;    Trastuzumab emtansine;    Pertuzumab;    HER2-positive breast cancer;    KRISTINE;   

DOI  :  10.1186/s13058-022-01587-z

 received in 2022-04-22, accepted in 2022-12-02,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundKRISTINE is an open-label, phase III study of trastuzumab emtansine + pertuzumab (T-DM1 + P) versus docetaxel + carboplatin + trastuzumab + pertuzumab (TCH + P) in patients with HER2-positive, stage II–III breast cancer. We investigated the association of biomarkers with clinical outcomes in KRISTINE.MethodsPatients were randomized to receive neoadjuvant T-DM1 + P or TCH + P and assessed for pathologic complete response (pCR; ypT0/is, ypN0). HER2 status (per central assessment), hormone receptor status, PIK3CA mutation status, HER2/HER3 mRNA levels, tumor-infiltrating lymphocyte levels, PD-L1 status, and NanoString data were analyzed. pCR rates by treatment arm were compared across biomarker subgroups. Analyses were descriptive.ResultsBiomarker analyses included data from all 444 patients (T-DM1 + P, n = 223; TCH + P, n = 221) enrolled in KRISTINE. Biomarker distribution was balanced across treatment arms. All subgroups with higher HER2 amplification/expression and immune marker levels showed numerically higher pCR rates in both arms. Mutated versus non-mutated PIK3CA tumors were associated with numerically lower pCR rates in the T-DM1 + P arm but not in the TCH + P arm. In a multivariate analysis, Prediction Analysis of Microarray with the 50-gene classifier (PAM50) HER2-enriched subtype, HER2 gene ratio ≥ 4, and PD-L1-positive status positively influenced the pCR rate. Biomarkers associated with lower pCR rates (e.g., low HER2 levels, positive hormone receptor status, mutated PIK3CA) were more likely to co-occur. Dynamic on-treatment biomarker changes were observed. Differences in the treatment effects for T-DM1 + P versus TCH + P were similar to those observed in the intent-to-treat population for the majority of the biomarker subgroups.ConclusionsAlthough our biomarker analysis did not identify a subgroup of patients that benefited from neoadjuvant T-DM1 + P versus TCH + P, the data revealed that patients with higher HER2 amplification/expression and immune marker levels had improved response irrespective of treatment arm. These analyses confirm the role of HER2 tumor biology and the immune microenvironment in influencing pCR in the neoadjuvant setting and reaffirm the molecular diversity of HER2-positive breast cancer.Trial Registration: ClinicalTrials.gov NCT02131064. Registered 06 May 2014.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

41116_2022_35_Article_IEq272.gif

41116_2022_35_Article_IEq259.gif

41116_2022_35_Article_IEq254.gif

Fig. 42