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

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

doi:10.3389/fonc.2021.686776

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

Front Oncol. 2021 Jun 28:11:686776. doi: 10.3389/fonc.2021.686776. eCollection 2021.

Authors

Francesco Schettini^{1

2}, Silvia Paola Corona^{3

4}, Fabiola Giudici^{3

5}, Carla Strina⁴, Marianna Sirico⁴, Ottavia Bernocchi^{3

4}, Manuela Milani⁴, Nicoletta Ziglioli⁴, Sergio Aguggini⁴, Carlo Azzini⁴, Giuseppina Barbieri⁴, Valeria Cervoni⁴, Maria Rosa Cappelletti⁴, Alfredo Molteni⁶, Maria Chiara Lazzari⁶, Giuseppina Ferrero⁷, Marco Ungari⁷, Elena Marasco⁸, Alice Bruson⁸, Luciano Xumerle⁸, Elisa Zago⁸, Davide Cerra⁸, Marco Loddo⁹, Gareth H Williams⁹, Ida Paris^{10

11}, Giovanni Scambia^{10

11}, Daniele Generali^{3

4}

Affiliations

¹ Translational genomics and targeted therapies in solid tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
² Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
³ Department of Medicine, Surgery and Health Sciences, University of Trieste, Cattinara Hospital, Trieste, Italy.
⁴ Multidisciplinary Unit of Breast Pathology and Translational Research, Cremona Hospital, Cremona, Italy.
⁵ Unit of Biostatistics, Epidemiology and Public Health, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy.
⁶ Unitá Operativa Ematologia e CTMO, Azienda Socio-Sanitaria Territoriale di Cremona, Cremona, Italy.
⁷ UO Anatomia Patologica ASST di Cremona, Cremona, Italy.
⁸ Personal Genomics Ltd, Verona, Italy.
⁹ Oncologica UK Ltd, Cambridge, United Kingdom.
¹⁰ Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Roma, Italy.
¹¹ Department of Woman and Child Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.

Abstract

Introduction: Olaparib is effective in metastatic triple negative breast cancer (TNBC) carrying germline mutations in DNA damage repair (DDR) genes BRCA1/2 (gBRCA-mut). The OLTRE window-of-opportunity trial preliminarily investigated potential pathologic, radiometabolic and immune biomarkers of early-response to olaparib in gBRCA-wild-type (wt) TNBC and, as proof-of-concept in gBRCA-mut HER2-negative BC.

Methods: Patients received olaparib for 3 weeks (3w) before standard neoadjuvant chemotherapy and underwent multiple FDG¹⁸-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.

Results: 27 patients with gBRCA-wt TNBC and 8 with gBRCA-mut BC (6 TNBC, 2 HR+/HER2-negative) were enrolled. Three (11.1%) patients showed mutations in non-BRCA1/2 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% gBRCA-wt patients. gBRCA-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<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 gBRCA status and type of response.

Conclusions: Early-stage TNBC might be a target population for olaparib, irrespective of gBRCA mutations. Future trials should combine TILs, PD-L1 and gBRCA status to better identify candidates for escalated/de-escalated treatment strategies including olaparib.

Keywords: BRCA; PD-L1; TILs; homologous recombination deficiency; neoadjuvant; olaparib (Lynparza™); triple negative breast cancer; window of opportunity clinical trial.

Copyright © 2021 Schettini, Corona, Giudici, Strina, Sirico, Bernocchi, Milani, Ziglioli, Aguggini, Azzini, Barbieri, Cervoni, Cappelletti, Molteni, Lazzari, Ferrero, Ungari, Marasco, Bruson, Xumerle, Zago, Cerra, Loddo, Williams, Paris, Scambia and Generali.