Abstract P5-04-28: Subtype by PAM50 changes after Neoadjuvant Endocrine therapy, from A Phase III Randomized, Double-Blind, Neoadjuvant Study of Hormonal Therapy plus Palbociclib versus Hormonal Therapy plus Placebo in ER+HER2- Operable Breast Cancer

Abstract Background: Luminal B breast cancer has heterogeneity which leads to unmet medical needs for cure. HER2-enriched type identified by PAM50 is occasionally found in luminal B subtype breast cancer by immunohistochemistry, leading to resistance to endocrine therapy (ET). To understand biological change following ET and to predict efficacy of ET, and consider additional therapies, we analyzed sequential samples from a neoadjuvant ET trial for exploratory analysis. Patients and Methods: This study was conducted as translational research for a phase III randomized, double-blind study of neoadjuvant hormonal therapy with or without palbociclib in untreated pre/peri- and post-menopausal women with operable, hormone receptor-positive (estrogen receptor and/or progesterone receptor), HER2-negative breast cancer (NCT03969121). Other major inclusion criteria included tumor size ≥ 15mm, T1c-3N0-1, Ki67 LI ≥14% by central assessment, and no previous history of radiotherapy or systemic therapy for breast cancer. Patients were randomly assigned 1:1 to receive 16 weeks of hormonal therapy plus palbociclib (125mg/day, 3W1R) or hormonal therapy plus placebo. Hormonal therapy consisted of letrozole for post-menopausal patients and tamoxifen plus LH-RH agonist for pre/peri-menopausal patients. The co-primary endpoints included PEPI score and EPclin Risk Score, a score combining EndoPredict® molecular score with clinical factors. The primary outcome was reported previously that the addition of palbociclib to neoadjuvant hormonal therapy did not improve efficacy measured by PEPI score. From 141 cases in the trial, 60 samples from 20 cases, who had sufficient tissue from biopsies at screening, cycle 1 day 15 (C1D15) and surgery, were analyzed by PAM50 for intrinsic subtype and risk of recurrence (ROR). Result: The distribution of cases (subtype and Ki-67) is shown in Table 1 and 2. Among 20 cases, 13 cases were in Palbociclib arm, and 7 in Placebo arm. There were 3 Her2-enriched cases in Palbociclib group (1 case at both screening and surgery, 1 case at screening only, 1 case at surgery only). As for ROR, there were no low-risk cases, 4 intermediate-risk cases, and 16 high-risk cases at screening. There was a shift to lower scores at C1D15: 10 low-risk cases, 9 intermediate-risk cases, and 1 high-risk cases. By surgery, however there seemed to be some rebound, but still lower than before treatment: 8 low-risk cases, 6 intermediate-risk cases, and 6 high-risk cases. Average of ROR was 69 at screening, 33 at C1D15, and 38 at surgery. In analysis of 17 luminal A/B cases (without 3 HER2-enrich cases), baseline data are not significantly different between Palbociclib arm and Placebo arm. Ki-67 at C1D15 was lower in palbociclib arm than in placebo arm (Average 1.5% (95% CI 0.4-3.4), 6.0% (1.5-10.6) respectively, p=0.027). At surgery, there were 8 PR cases and 2 SD cases in palbociclib arm, 3 PR cases and 4 SD cases in placebo arm. There were no significant differences between the two arms in Ki67(%), PEPI score, EP clin risk score and ROR at surgery. Conclusion: Neoadjuvant endocrine therapy for 16 weeks changes subtype classification by PAM50 from luminal B to luminal A and the ROR drastically. Greater effects were noted for the combination, not statistically significant, but this warrants further investigation in a larger cohort. There were 3 HER2-enriched cases with poor response, but this was not significant because of the small sample size. These 3 cases probably reflect tumor heterogeneity on the baseline biopsy. Neoadjuvant 16 weeks endocrine therapy may work to screen for ET resistance, and help select a switch in therapy, or those benefitting most from Palbociclib. Further research will be necessary including PAM50, Oncotype Dx and those with high Ki67. Clinical trial identification: NCT03969121 Funding: Pfizer Inc. Citation Format: Rie Nakagawa, Nobuko Kawaguci-Sakita, Adrian Harris, Takayuki Ueno, Louis Chow, Wonshik Han, Chiun-Sheng Huang, Gregory Bruce Mann, Satoshi Morita, Masakazu Toi, Hironori Haga, Masahiro Takada, Shigeru Imoto, Yuko Tanabe, Toshinari Yamashita, Hiroji Iwata, Hiroko Bando, Hirofumi Suwa, Eriko Tokunaga, Yasuaki Sagara, Norikazu Masuda, Elham Fakhrejahani. Subtype by PAM50 changes after Neoadjuvant Endocrine therapy, from A Phase III Randomized, Double-Blind, Neoadjuvant Study of Hormonal Therapy plus Palbociclib versus Hormonal Therapy plus Placebo in ER+HER2- Operable Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-04-28.