TY - JOUR
T1 - Clinical, Radiometabolic and Immunologic Effects of Olaparib in Locally Advanced Triple Negative Breast Cancer
T2 - The OLTRE Window of Opportunity Trial
AU - Schettini, Francesco
AU - Corona, Silvia Paola
AU - Giudici, Fabiola
AU - Strina, Carla
AU - Sirico, Marianna
AU - Bernocchi, Ottavia
AU - Milani, Manuela
AU - Ziglioli, Nicoletta
AU - Aguggini, Sergio
AU - Azzini, Carlo
AU - Barbieri, Giuseppina
AU - Cervoni, Valeria
AU - Cappelletti, Maria Rosa
AU - Molteni, Alfredo
AU - Lazzari, Maria Chiara
AU - Ferrero, Giuseppina
AU - Ungari, Marco
AU - Marasco, Elena
AU - Bruson, Alice
AU - Xumerle, Luciano
AU - Zago, Elisa
AU - Cerra, Davide
AU - Loddo, Marco
AU - Williams, Gareth H.
AU - Paris, Ida
AU - Scambia, Giovanni
AU - Generali, Daniele
N1 - Funding Information:
The study has been conducted with Astra-Zeneca contribution. The funder had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. This research was also supported by Mednote, spin-off - University of Trieste - Mozart Program.
Funding Information:
The authors want to gratefully thank all patients and their respective families involved in the present study. FS is recipient of an ESMO Fellowship – Translational.
Funding Information:
Conflict of Interest: 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.
Publisher Copyright:
© 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.
PY - 2021/6/28
Y1 - 2021/6/28
N2 - 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.
AB - 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.
KW - BRCA
KW - homologous recombination deficiency
KW - neoadjuvant
KW - olaparib (Lynparza™)
KW - PD-L1
KW - TILs
KW - triple negative breast cancer
KW - window of opportunity clinical trial
UR - http://www.scopus.com/inward/record.url?scp=85109781196&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85109781196&partnerID=8YFLogxK
U2 - 10.3389/fonc.2021.686776
DO - 10.3389/fonc.2021.686776
M3 - Article
AN - SCOPUS:85109781196
SN - 2234-943X
VL - 11
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 686776
ER -