Abstract PS5-14: Gene-expression profiling and response to neoadjuvant endocrine treatment in the phase II LETLOB trial
Authors: Griguolo Gaia , Dieci Maria Vittoria , Generali Daniele Giulio , Paré Laia , Frassoldati Antonio , Cavanna Luigi , Tagliafico Enrico , Cagossi Katia , Bisagni Giancarlo , Piacentini Federico , Miglietta Federica , Ficarra Guido , Prat Aleix , Conte PierFranco , Guarneri Valentina 
Published: February 2021

Abstract
Background: Hormone receptor positive (HR+)/HER2- breast cancer (BC) is a clinically and biologically heterogeneous disease, encompassing all BC molecular intrinsic subtypes. We here explore the association between gene-expression profiles and response to neoadjuvant endocrine-based treatment in early HR+/HER2- BC.
Methods: The LETLOB phase II trial randomized 92 postmenopausal women with clinical stage II-IIIA HR+/HER2- BC to receive neoadjuvant letrozole + lapatinib or letrozole + placebo for 6 months. Objective response was the primary endpoint, as defined by study protocol and previously published (Guarneri, JCO 2014). Gene-expression data (Affymetrix platform) from pre-treatment frozen core-biopsies was available for 66 pts. Intrinsic subtype was assigned using a research-based PAM50 subtype predictor. The PAM50 based chemo-endocrine score (CES) was calculated using published definition (Prat, CCR 2017). Higher values of CES indicate increased endocrine sensitivity, while lower values indicate higher chemosensitivity.
Results: Intrinsic subtype distribution was as follows: Luminal A 39% (N=25), Luminal B 36% (N=24), HER2-enriched 8% (N=5), basal-like 18% (N=12). Non-luminal tumors (basal-like and HER2-enriched) were characterized by less differentiated histological grades (Grade 3 65% vs 33%, p=0.037) and higher Ki67 expression at baseline as compared to luminal tumors (median 20% vs 15%, p=0.013). Considering both treatment arms combined, non-luminal tumors showed a significantly lower objective response rate as compared to luminal tumors (47% vs 78%, p=0.031). This difference was statistically significant in the lapatinib arm (43% vs 90%, p=0.021), but not in the placebo arm (50% vs 68%, p=0.449; interaction test p=0.169). After treatment, non-luminal tumors had significantly higher Ki67 levels than luminal ones (post-treatment median 10% and 7%, respectively, p=0.004).
Median CES level at baseline was -0.03 (range: -1.11, +1.12). Each unit increase in CES levels at baseline was numerically associated with higher probability of achieving an objective response (Odds Ratio 1.95, 95% CI 0.74-5.18, p=0.178, both arms combined).
Conclusions: In HR+/HER2- early BC patients enrolled in the LET-LOB trial, patients with non-luminal tumor or low CES score showed reduced sensitivity to endocrine-based treatment. The highest response rate (90%) was observed in luminal patients treated with letrozole + lapatinib. Gene-expression profiling could potentially be used to identify patients with low sensitivity to endocrine treatment for which neoadjuvant chemotherapy should be preferred.
Citation Format: Gaia Griguolo, Maria Vittoria Dieci, Daniele Giulio Generali, Laia Paré, Antonio Frassoldati, Luigi Cavanna, Enrico Tagliafico, Katia Cagossi, Giancarlo Bisagni, Federico Piacentini, Federica Miglietta, Guido Ficarra, Aleix Prat, PierFranco Conte, Valentina Guarneri. Gene-expression profiling and response to neoadjuvant endocrine treatment in the phase II LETLOB trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-14.