AUTHOR=Schettini Francesco , Corona Silvia Paola , Giudici Fabiola , Strina Carla , Sirico Marianna , Bernocchi Ottavia , Milani Manuela , Ziglioli Nicoletta , Aguggini Sergio , Azzini Carlo , Barbieri Giuseppina , Cervoni Valeria , Cappelletti Maria Rosa , Molteni Alfredo , Lazzari Maria Chiara , Ferrero Giuseppina , Ungari Marco , Marasco Elena , Bruson Alice , Xumerle Luciano , Zago Elisa , Cerra Davide , Loddo Marco , Williams Gareth H. , Paris Ida , Scambia Giovanni , Generali Daniele 

TITLE=Clinical, Radiometabolic and Immunologic Effects of Olaparib in Locally Advanced Triple Negative Breast Cancer: The OLTRE Window of Opportunity Trial

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.686776

DOI=10.3389/fonc.2021.686776

ISSN=2234-943X

ABSTRACT=<sec><title>Introduction</title><p>Olaparib is effective in metastatic triple negative breast cancer (TNBC) carrying germline mutations in DNA damage repair (DDR) genes <italic>BRCA1/2</italic> (g<italic>BRCA</italic>-mut). The OLTRE window-of-opportunity trial preliminarily investigated potential pathologic, radiometabolic and immune biomarkers of early-response to olaparib in g<italic>BRCA</italic>-wild-type (wt) TNBC and, as proof-of-concept in g<italic>BRCA</italic>-mut HER2-negative BC.</p></sec><sec><title>Methods</title><p>Patients received olaparib for 3 weeks (3w) before standard neoadjuvant chemotherapy and underwent multiple FDG<sup>18</sup>-PET/CT scan (basal, after olaparib), clinical assessments (basal, every 3w), tumor biopsies and blood samplings (baseline, after olaparib). Clinical and radiometabolic responses were evaluated according to RECIST1.1 and PERCIST criteria.</p></sec><sec><title>Results</title><p>27 patients with g<italic>BRCA</italic>-wt TNBC and 8 with g<italic>BRCA</italic>-mut BC (6 TNBC, 2 HR+/HER2-negative) were enrolled. Three (11.1%) patients showed mutations in non-<italic>BRCA</italic>1/2 DDR genes and 4 (14.8%) in other genes. 3w olaparib induced 16/35 and 15/27 partial clinical and radiometabolic responses, including in 40.7% and 50.0% g<italic>BRCA</italic>-wt patients. g<italic>BRCA</italic>-mut tumors presented numerically higher tumor-infiltrating lymphocytes (TILs) levels and PD-L1 positive tumors. Clinical responders experienced a reduction in T-regs/T-eff ratio (p=0.05), B and NK lymphocytes (p=0.003 both), with an average increase in T-helpers rate (p&lt;0.001) and CD4/CD8 ratio (p=0.02). Ki67% and TILs did not vary significantly (p=0.67 and p=0.77). A numerical increase in PD-L1 positive cases after olaparib was observed, though non-significant (p=0.134). No differences were observed according to g<italic>BRCA</italic> status and type of response.</p></sec><sec><title>Conclusions</title><p>Early-stage TNBC might be a target population for olaparib, irrespective of g<italic>BRCA</italic> mutations. Future trials should combine TILs, PD-L1 and g<italic>BRCA</italic> status to better identify candidates for escalated/de-escalated treatment strategies including olaparib.</p></sec>