Frontiers in Oncology (Jun 2021)

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

  • Francesco Schettini,
  • Francesco Schettini,
  • Silvia Paola Corona,
  • Silvia Paola Corona,
  • Fabiola Giudici,
  • Fabiola Giudici,
  • Carla Strina,
  • Marianna Sirico,
  • Ottavia Bernocchi,
  • 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,
  • Ida Paris,
  • Giovanni Scambia,
  • Giovanni Scambia,
  • Daniele Generali,
  • Daniele Generali

DOI
https://doi.org/10.3389/fonc.2021.686776
Journal volume & issue
Vol. 11

Abstract

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IntroductionOlaparib 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.MethodsPatients 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.Results27 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.ConclusionsEarly-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.

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