Abstract P6-07-09: Biomarker analysis from the neoadjuvant KRISTINE study in HER2-positive early breast cancer (EBC)
Authors: de Haas SL , Hurvitz SA , Martin M , Kiermaier A , Lewis Phillips G , Xu J , Helms H-J , Slamon D , Press MF 
Published: March 2017

Introduction KRISTINE (NCT02131064) is an open-label, phase 3 study of neoadjuvant trastuzumab emtansine + pertuzumab (T-DM1+P) vs docetaxel + carboplatin + trastuzumab + pertuzumab (TCH+P) in pts with HER2+ EBC (all pts, Table). In exploratory analyses we assessed whether HER2 expression and gene amplification levels and PIK3CA mutation were associated with pathologic complete response (pCR) in KRISTINE.

Methods Treatment-naive pts with stage II–IIIC HER2+ EBC were randomized to receive 6 cycles of T-DM1+P or TCH+P and assessed for the primary endpoint, pCR (ypT0/is, ypN0). HER2 status was confirmed centrally as immunohistochemistry (IHC) status of IHC3+ and/or HER2/CEP17 gene ratio ≥2 by in situ hybridization (ISH) before study entry. Baseline HER2 mRNA, PIK3CA mutation, and hormone receptor (HR) status were evaluated. Rates of pCR were compared across biomarker subgroups, including: HER2 mRNA, HER2 IHC staining percentage, HER2 gene ratio, and PIK3CA mutation. Incidence of overlap between biomarkers was assessed. All analyses were descriptive.

Results KRISTINE randomized 444 pts (data cutoff, Dec 3, 2015; TCH+P=221; T-DM1+P=223). The biomarker population was representative of the ITT population. Biomarker values and distribution were balanced across treatment arms. Lower pCR rates were seen in both treatment arms across biomarker subgroups with lower vs higher HER2 expression levels (Table). PIK3CA mutation was associated with numerically lower pCR with T-DM1+P but not TCH+P. Evaluation of 15 pts who progressed during T-DM1+P neoadjuvant therapy suggests that nonresponse to therapy in this arm may be associated with low HER2 levels (mRNA, IHC, and ISH).

PIK3CA mutation rate was higher in tumors with ≤median HER2 mRNA (38%) vs &gt;median (16%), and in focal (53%) and variable (41%) HER2 expression vs homogeneous (24%). A numerically higher proportion of HR positivity was seen in the HER2 IHC2+ (81%) subgroup vs IHC3+ (55%), and in the focal (83%) and variable (62%) HER2 subgroups vs homogeneous (53%).

Table TCH+PT-DM1+P  BiomarkernpCR (%)npCR (%)Difference in pCR rates (%)95% CIAll pts22155.722344.4-11.3-20.5, -2.0HER2      IHC3+19460.819549.7-11.1-20.9, -1.3IHC2+2520.0287.1-12.9-31.2, 5.5HER2 IHC 2+/3+ fraction*      Focal (&lt;30%)1533.3160-33.3-57.2, -9.5Variable (30–79%)2729.62722.2-7.4-30.7, 15.9Homogeneous (≥80%)17961.518051.7-9.8-20.0, 0.4HER2 mRNA expression      ≤median10649.110937.6-11.4-24.6, 1.7&gt;median10763.610851.9-11.7-24.8, 1.4HER2/CEP17 gene ratio      ≥2 to &lt;44533.35219.2-14.1-31.6, 3.4≥416662.015853.2-8.9-19.6, 1.8PIK3CA mutation      Mutated5354.76131.1-23.6-41.3, -5.8Nonmutated16056.315151.0-5.3-16.3, 5.8*Categorization based on sum of IHC2+ and IHC3+ staining percentage.

Conclusions None of the evaluated biomarker subgroups showed superior pCR rates for T-DM1+P vs TCH+P. Lower HER2 levels based on mRNA and protein expression and gene amplification were associated with numerically lower pCR in both treatment arms. PIK3CA mutation results differ from prior observations. Unfavorable biomarkers for pCR, like low HER2, PIK3CA mutation, and HR positivity, showed a tendency for co-expression, which should be considered when planning future trials in HER2+ BC.

Citation Format: de Haas SL, Hurvitz SA, Martin M, Kiermaier A, Lewis Phillips G, Xu J, Helms H-J, Slamon D, Press MF. Biomarker analysis from the neoadjuvant KRISTINE study in HER2-positive early breast cancer (EBC) [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 P6-07-09.