Abstract
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.
Highlights
Olaparib is effective in metastatic triple negative breast cancer (TNBC) carrying germline mutations in DNA damage repair (DDR) genes BRCA1/2
Three (11.1%) patients showed mutations of genes involved in the DDR pathways (i.e. BARD1, MSH2-3, RAD51C, PMS2 and ATM) and 4 (14.8%) carried mutations in genes other than the ones implicated in DDR (i.e. PTEN, AXIN2, APC, GALNT12), 2 of which of unknown clinical significance (Supplementary Table 1)
OLTRE was a WoO trial that aimed to assess primarily the biologic, immunologic and genetic changes that olaparib might induce in germline BRCA1/2 (gBRCA)-wild type TNBC, with a small cohort of HER2negative gBRCA-mutant tumors as proof-of-concept
Summary
Olaparib is effective in metastatic triple negative breast cancer (TNBC) carrying germline mutations in DNA damage repair (DDR) genes BRCA1/2 (gBRCA-mut). Triple Negative breast cancer (TNBC) is a heterogenous subgroup of prognostically unfavorable breast tumors, in urgent need for new personalized therapeutic approaches, as chemotherapy still remains their mainstay of treatment, due to the lack of well-defined molecular targets [5] In this perspective, a common characteristic of TNBC is the reduced expression of DNA damage repair (DDR) genes, with BRCA1/2 being the most frequently affected [6]. While in ovarian cancer these agents demonstrated activity irrespective of the presence of a BRCA mutation [10, 11], it is still unclear if the use of PARPi could be extended to BRCA-wild type TNBC, as the few studies trying to address this question provided equivocal results [12,13,14,15,16] For this reason, we conducted the trial OLTRE. As a proof of concept, analyses were performed separately in a small group of gBRCA-mutant hormone receptor-positive (HR+) BC and TNBC, in which sensitivity to olaparib has already been proven [8]
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