Abstract 4377
Background
The ALTERNATIVE trial randomized 355 patients (pts) with HER2+/HR+ metastatic BC to receive as 1st-line therapy lapatinib (L) + trastuzumab (T) + aromatase inhibitors (AI) or T + AI or L + AI. The neoadjuvant PAMELA trial tested a chemo-free regimen of L + T on HER2+ pts, combined with letrozole or tamoxifen in HR+ tumors. We explored the hypothesis that gene expression may help predicting benefit from anti-HER2 therapy in combination with ET.
Methods
The expression of 55 BC-related genes was evaluated from FFPE tumors using the nCounter. The PAM50 subtype distribution and the association of the expression of each gene (continuous variable) with progression-free survival (PFS) was evaluated using univariate Cox-models. Median PFS was calculated using the Kaplan-Meier method. Clinical benefit (CB) was defined as complete or partial response or stable disease at 6 months. The Cutoff Finder tool was used to find an optimal gene expression cut-off with CB as the endpoint. Logistic regression was used to evaluate the association of gene expression with pathologic complete resonse (pCR) and CB.
Results
In ALTERNATIVE, 60 tumors (16.9%) were analyzed: 57% HER2-enriched, 20% Luminal B, 12% Luminal A, 8% Normal-like and 3% Basal-like. Median PFS in ERBB2-high group (above the median) was higher compared to ERBB2-low group (11.0 vs 5.6 months; Hazard Ratio [HazR]=0.49; p = 0.006). ERBB2 was found more expressed in pts with CB. CB rate was higher in the ERBB2-high group compared to ERBB2-low group (54% vs 22%; p = 0.013). An optimal ERBB2 mRNA cutoff (2.923) for predicting CB (AUC=0.68; odds ratio [OR]=1.49, p = 0.014; PFS HazR=0.46, p = 0.022) was then identified. The same ERBB2 cutoff in PAMELA baseline tumor samples (n = 77) was found significantly associated with pCR (43.8% in ERBB2-high vs. 11.5% in ERBB2-low; adjusted OR = 4.45; p = 0.041).
Conclusions
ERBB2 mRNA expression is a robust predictor of response and survival outcome in HER2+/HR+ BC following HER2-blockade and ET. Our study identifies a common biomarker between pCR improvement (OR ∼4.5) in early disease and CB in the advanced setting (PFS HazR of ∼0.50).
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Institut d’investigacions Biomèdiques August Pi i Sunyer (IDIBAPS).
Funding
Has not received any funding.
Disclosure
N. Chic: Travel / Accommodation / Expenses: Eisai. F. Schettini: Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Pfizer. M. Vidal: Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Eisai; Speaker Bureau / Expert testimony: Daiichi Sankyo. M. Muñoz: Travel / Accommodation / Expenses: Roche. J. Cortés: Honoraria (self): Novartis; Honoraria (self): Eisai; Honoraria (self): Roche; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Celgene; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Biothera Pharmaceutical; Advisory / Consultancy: Merus; Advisory / Consultancy: Seattle Genetics. A. Llombart-Cussac: Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche/Genentech. M. Rimawi: Advisory / Consultancy: GlaxoSmithKline; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: MacroGenics; Advisory / Consultancy: Novartis; Advisory / Consultancy: Daiichi Sankyo. A. Prat: Advisory / Consultancy: Nanostring Techonologies. All other authors have declared no conflicts of interest.
Resources from the same session
3264 - A novel preclinical model of RAF-independent MEK1 mutant tumors and its treatment with novel ATP competitive MEK inhibitor
Presenter: Luca Hegedus
Session: Poster Display session 3
Resources:
Abstract
4918 - HER2 inhibition in Aggressive Squamous Cell Carcinomas driven by a common MET Sema Domain Polymorphism
Presenter: Nur Afiqah Mohamed Salleh
Session: Poster Display session 3
Resources:
Abstract
2426 - ADAM9 as a target for lung cancer treatment
Presenter: Yuh-pyng Sher
Session: Poster Display session 3
Resources:
Abstract
5537 - Novel polyurea/polyurethane nanocapsules loaded with a tambjamine analog to improve cancer chemotherapy delivery and safety in lung cancer
Presenter: Marta Perez Hernandez
Session: Poster Display session 3
Resources:
Abstract
1597 - Discovery of Clinical Candidate DBPR112, a Furanopyrimidine-based Epidermal Growth Factor Receptor Inhibitor for the Treatment of Non-Small Cell Lung Cancer
Presenter: Hsing-pang Hsieh
Session: Poster Display session 3
Resources:
Abstract
3543 - Molecular characteristics in lung squamous cell carcinomas dependent on TP53 status – putative targets
Presenter: Vilde Haakensen
Session: Poster Display session 3
Resources:
Abstract
4111 - Comparison of molecular profiles between primary tumour and matched metastasis in non-small cell lung cancer
Presenter: Asuka Kawachi
Session: Poster Display session 3
Resources:
Abstract
4559 - Treatment with BLU-667, a potent and selective RET inhibitor, provides rapid clearance of ctDNA in Patients with RET-altered Non-Small Cell Lung Cancer (NSCLC) and Thyroid Cancer
Presenter: Giuseppe Curigliano
Session: Poster Display session 3
Resources:
Abstract
2501 - Triple MET/SRC/PIM inhibition in MET addicted tumors
Presenter: Ilaria Attili
Session: Poster Display session 3
Resources:
Abstract
5655 - Bioactivation of napabucasin triggers reactive oxygen species–mediated cancer cell death
Presenter: Fieke Froeling
Session: Poster Display session 3
Resources:
Abstract