Abstract CT026: The effect of intrinsic subtype on inhibition of tumor growth by anastrozole vs. fulvestrant vs. the combination: Results from the Alliance neoadjuvant endocrine therapy (NET) ALTERNATE trial

• Published in: Cancer research (Chicago, Ill.) Ill.), 2022-06, Vol.82 (12_Supplement), p.CT026-CT026
• Main Authors: Ellis, Matthew J., Anurag, Meenakshi, Hoog, Jeremy, Fernandez-Martinez, Aranzazu, Fan, Cheng, Gibbs, Richard, Sanati, Souzan, Vij, Kiran, Watson, Mark, Dockter, Travis, Hahn, Olwen, Guenther, Joseph, Caudle, Abigail, Crouch, Erica, Tiersten, Amy, Mita, Monica, Razaq, Wajeeha, Hieken, Tina J., Wang, Yang, Leitch, A. Marilyn, Unzeitig, Gary W., Winer, Eric, Weiss, Anna, Hunt, Kelly, Partridge, Ann H., Perou, Charles M., Suman, Vera, Ma, Cynthia X., Carey, Lisa A.
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2022-CT026

Introduction: The ALTERNATE trial randomized postmenopausal women with ER Allred 6-8 HER2- breast cancer to 6 months of NET with anastrozole (A), fulvestrant (F) or the combination (A+F). Biopsies were taken preNET and after 4-weeks(wks). Patients with Ki67 values >10% at 4-wks were offered triage to neoadjuvant chemotherapy. Patients with on-treatment Ki67 ≤ 10% who completed NET underwent surgery and Ki67 was reassessed. The primary endpoint was endocrine-sensitive disease rate (ESDR). ESD is defined as pCR or PEPI-0 residual disease (pT1-2, pN0, Ki67 ≤ 2.7%). We previously reported that the ESDR difference between the F-containing arms and the A arm was not >10% (ASCO 2020) and that baseline RNA-seq-based intrinsic subtypes predicted outcomes overall (SABCS 2021). Herein we describe relationships between PAM50 intrinsic subtype and Ki67 values by treatment arm because comparative drug effectiveness in adjuvant endocrine therapy studies in ER+ HER2- breast cancer can be predicted by the degree of Ki67 suppression (PMC3518447). Methods: 743 of the 1297 eligible patients (A: 264; F: 231; A+F: 248) had RNA extracted from preNET frozen tumor biopsies with >50% tumor content and subjected to RNA seq. Intrinsic subtypes were then assigned as LumA, LumB, and NonLum (Basal or HER2-E) using open-source PAM50-based informatics. Differences in the proportion with wk4 Ki67 > 10%, % change in wk4 ki67, and surgical CCCA (Ki67 ≤ 2.7%) rate (sxCCCA) between treatments and by intrinsic subtype was assessed using stratified logistic regression, Wilcoxon rank sum test, and Fisher’s exact test, respectively. Analysis of sxCCCA excluded those who failed to complete NET for reasons other than disease progression or early Ki67 >10%. Results: Amongst the 358 LumA cases there were no significant differences in Ki67-based endpoints between treatments. Among the 292 LumB cases, the wk4 ki67 > 10% rate was lower with A+F (19.4%) than A (43%) (P=0.0002) and was somewhat lower in F (31%) versus A (P=0.076). The % change in wk4 Ki67 in LumB cases, adjusted for baseline Ki67, showed markedly superior suppression for A+F versus A (-90% vs. -77%; P=