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

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

Francesco Schettini  1   2 , Silvia Paola Corona  3   4 , Fabiola Giudici  3   5 , Carla Strina  4 , Marianna Sirico  4 , Ottavia Bernocchi  3   4 , Manuela Milani  4 , Nicoletta Ziglioli  4 , Sergio Aguggini  4 , Carlo Azzini  4 , Giuseppina Barbieri  4 , Valeria Cervoni  4 , Maria Rosa Cappelletti  4 , Alfredo Molteni  6 , Maria Chiara Lazzari  6 , Giuseppina Ferrero  7 , Marco Ungari  7 , Elena Marasco  8 , Alice Bruson  8 , Luciano Xumerle  8 , Elisa Zago  8 , Davide Cerra  8 , Marco Loddo  9 , Gareth H Williams  9 , Ida Paris  10   11 , Giovanni Scambia  10   11 , Daniele Generali  3   4
Affiliations

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

Francesco Schettini et al. Front Oncol. .

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.

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Conflict of interest statement

EM, AB, LX, EZ and DC were employed by Personal Genomics Ltd. GW and ML are employed at Oncologica UK Ltd., which has received project funding from AstraZeneca outside of the submitted work. DG has declared consulting fees from Novartis, Lilly and Pfizer, research funding from LILT, Novartis, Astra-Zeneca and University of Trieste outside of the submitted work. IP has declared consulting fees from Roche, Novartis, Lilly, Pfizer, Astra-Zeneca, Pierre Fabre and Ipsen outside of the submitted work. GS has declared Grant/Research Support from MSD Italia S.r.l., consulting role for TESARO Bio Italy S.r.l. Johnson & Johnson and Clovis Oncology Italy S.r.l., outside of the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
CONSORT diagram. TNBC, triple negative breast cancer; HR+, hormone receptor-positive; HER2neg., HER2-negative; gBRCA1/2, germline BRCA1 and BRCA2; SUV, standard uptake volume; TILs, tumor-infiltrating lymphocytes.
Figure 2
Figure 2
TILs and PD-L1 distribution in the overall population, gBRCA-mutant and wild-type tumors at basal assessment. TILs, tumor-infiltrating lymphocytes; gBRCA-wt, germinal BRCA1/2-wild type triple negative tumors; gBRCA-mut, germinal BRCA1/2-mutant tumors; PD-L1, PD-L1 in tumor-infiltrating inflammatory cells.
Figure 3
Figure 3
Clinical and radiometabolic responses. Waterfall plots of clinical (A, B) and radiometabolic (C, D) responses in the overall population and according to BRCA mutational status, along with bar plots (B, D) detailing response rates according to BRCA status. PR, partial response; SD, stable disease; PD, progressive disease; WT, wild-type.
Figure 4
Figure 4
Box plot for pre/post olaparib circulating immune cells levels in the overall population. Pre: before olaparib; Post: after 3 weeks of olaparib; Abs, absolute count. When abs not specified, the graphic is referred to %. Treg, Regulatory T lymphocytes; Teff, Effectors T Lymphocytes.
Figure 5
Figure 5
Mutational status according to clinical and radiometabolic response status. Only mutant genes are reported.
See this image and copyright information in PMC

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