Abstract P2-09-05: Independent validation of the PAM50-based chemo-endocrine score (CES) in hormonal receptor positive (HR+)/HER2+ breast cancer (BC) treated with neoadjuvant (NA) anti-HER2-based therapy
Authors: Pascual T , Tanioka M , Dieci MV , Pernas S , Gavila J , Guarnieri V , Cortes J , Llombart A , Conte P , Oliveira M , Paré L , Galván P , Perou CM , Prat A , Carey L 
Published: February 2018

Abstract
Background. HER2+/HR+ BC is heterogeneous and subgroups with different treatment sensitivities need to be identified. We previously reported a PAM50-based CES in HR+/HER2-negative BC (Prat et al. CCR 2016). Here, we evaluated the association of CES with pathologic complete response (pCR) following anti-HER2-based therapy in HR+/HER2+ BC across 6 NA studies.
Methods. Intrinsic subtype and clinico-pathological data were obtained from 6 NA clinical studies (CHERLOB, OptiHERHEART[OHH], PAMELA, LPT109096, ICO and CALGB 40601 [CALGB is part of the Alliance for Clinical Trials in Oncology]). All patients (pts) received chemotherapy (CT) and trastuzumab, except for pts in the PAMELA study who did not receive CT. A second anti-HER2 agent (lapatinib or pertuzumab) was included in the NA of all pts in OHH and PAMELA and in one of the treatment arms in CHERLOB, LPT and C40601. CES was evaluated as a continuous variable, and categorically (CES-E[endocrine-sensitive], CES-U[uncertain] and CES-C[chemo-sensitive]) using the previously reported cut-offs. In all studies, except CHERLOB and C40601, ERBB2 mRNA levels were measured using the nCounter platform. pCR in the breast was the endpoint. We first performed statistical analyses in each dataset individually, and then in a dataset with combined patient-level data. Univariate and multivariable logistic regressions analyses were used.
Results. A total of 345 pts were included in the analysis. In the combined cohort, CES-E, CES-U and CES-C were identified in 27.5%, 23.7% and 48.6% of the pts, respectively. Table 1 summarizes the distribution and pCR rates by CES groups. In the combined cohort, CES-C was associated with higher pCR rates compared to CES-U and CES-E independent of tumor size, nodal status, anti-HER2 treatment (single vs. dual HER2 blockade), intrinsic subtype (HER2-enriched [HER2E] versus not) and study (Table 2). In the PAMELA trial (no CT), CES-C was also found associated with higher pCR rates compared to CES-E (31.6% vs. 0%). Concordant with this finding, CES-C tumors showed higher ERBB2 mRNA levels than non-CES-C (P&lt;0.01).
Conclusion. CES shows clinical validity for predicting CT/HER2-targeting sensitivity in HER2+/HR+ BC beyond intrinsic subtype and clinicopathologic characteristics. HER2+/HR+/CES-E tumors, which represent ˜20% of all HER2+ tumors, show low sensitivity to anti-HER2 regimens (with and without CT); other treatment strategies might be needed for this group.
Support: U10CA180882;U10CA180821;U24CA196171;P50-CA58823;BCRF;Komen.
Table 1. Distribution and pCR rates of CES-E, CES-U and CES-C groups across studies.n(%pCR)LPTCHERLOBOHHICOPAMELAC40601TOTALCES-E00/9(0)1/5(20)0/7(0)0/14(0)16/60(27)17/95 (18)CES-U0/1(0)4/15(27)5/7(71)4/13(30)2/25(8)10/21(47)25/82 (30)CES-C20/29(69)12/32(37)22/28(78)15/29(52)12/38(32)3/6(50)84/162(52)P0.330.080.040.03&lt;0.01&lt;0.01&lt;0.01
Table 2. Association of CES, intrinsic subtype, clinicopathologic variables and study with pCR in a multivariable model (including type of study). OR95% CIPCES CES-E1 CES-U2.91.2-7.0&lt;0.01CES-C6.22.3-16.4&lt;0.01T3-4 vs T1-20.40.2-0.90.02N+ vs N00.90.4-1.70.68HER2E vs not2.21.1-4.30.02AntiHER2: 2vs12.90.7-3.20.20
Citation Format: Pascual T, Tanioka M, Dieci MV, Pernas S, Gavila J, Guarnieri V, Cortes J, Llombart A, Conte P, Oliveira M, Paré L, Galván P, Perou CM, Prat A, Carey L. Independent validation of the PAM50-based chemo-endocrine score (CES) in hormonal receptor positive (HR+)/HER2+ breast cancer (BC) treated with neoadjuvant (NA) anti-HER2-based therapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-05.