Olaparib monotherapy as primary treatment in unselected triple negative breast cancer
H P Eikesdal, S Yndestad, A Elzawahry, A Llop-Guevara, B Gilje, E S Blix, H Espelid, S Lundgren, J Geisler, G Vagstad, A Venizelos, L Minsaas, B Leirvaag, E G Gudlaugsson, O K Vintermyr, H S Aase, T Aas, J Balmaña, V Serra, E A M Janssen, S Knappskog, P E Lønning, H P Eikesdal, S Yndestad, A Elzawahry, A Llop-Guevara, B Gilje, E S Blix, H Espelid, S Lundgren, J Geisler, G Vagstad, A Venizelos, L Minsaas, B Leirvaag, E G Gudlaugsson, O K Vintermyr, H S Aase, T Aas, J Balmaña, V Serra, E A M Janssen, S Knappskog, P E Lønning
Abstract
Background: The antitumor efficacy of PARP inhibitors (PARPi) for breast cancer patients harboring germline BRCA1/2 (gBRCA1/2) mutations is well established. While PARPi monotherapy was ineffective in patients with metastatic triple negative breast cancer (TNBC) wild type for BRCA1/2, we hypothesized that PARPi may be effective in primary TNBCs without previous chemotherapy exposure.
Patients and methods: In the phase II PETREMAC trial, patients with primary TNBC >2 cm received olaparib for up to 10 weeks before chemotherapy. Tumor biopsies collected before and after olaparib underwent targeted DNA sequencing (360 genes) and BRCA1 methylation analyses. In addition, BRCAness (multiplex ligation-dependent probe amplification), PAM50 gene expression, RAD51 foci, tumor-infiltrating lymphocytes (TILs) and PD-L1 analyses were performed on pretreatment samples.
Results: The median pretreatment tumor diameter was 60 mm (range 25-112 mm). Eighteen out of 32 patients obtained an objective response (OR) to olaparib (56.3%). Somatic or germline mutations affecting homologous recombination (HR) were observed in 10/18 responders [OR 55.6%, 95% confidence interval (CI) 33.7-75.4] contrasting 1/14 non-responders (OR 7.1%; CI 1.3-31.5, P = 0.008). Among tumors without HR mutations, 6/8 responders versus 3/13 non-responders revealed BRCA1 hypermethylation (P = 0.03). Thus, 16/18 responders (88.9%, CI 67.2-96.9), in contrast to 4/14 non-responders (28.6%, CI 11.7-54.7, P = 0.0008), carried HR mutations and/or BRCA1 methylation. Excluding one gPALB2 and four gBRCA1/2 mutation carriers, 12/14 responders (85.7%, CI 60.1-96.0) versus 3/13 non-responders (23.1%, CI 8.2-50.3, P = 0.002) carried somatic HR mutations and/or BRCA1 methylation. In contrast to BRCAness signature or basal-like subtype, low RAD51 scores, high TIL or high PD-L1 expression all correlated to olaparib response.
Conclusion: Olaparib yielded a high clinical response rate in treatment-naïve TNBCs revealing HR deficiency, beyond germline HR mutations.
Trial registration: ClinicalTrials.gov identifier: NCT02624973.
Keywords: PARP inhibitor; homologous recombination deficiency; neoadjuvant therapy; olaparib; prediction; triple negative breast cancer.
Conflict of interest statement
Disclosure Research Funding (to Institution): Astellas Oncology (BG), AstraZeneca (HPE, BG, JB, VS, SK, PEL), Celgene (BG), Novartis (HPE, VS, PEL), Pfizer (HPE, SK, BG, JB, PEL), Tesaro (VS), Zenith Pharmaceuticals (VS). Honoraria: Amgen (HPE), AstraZeneca (HPE, BG, TA, EAMJ, SK, PEL), AbbVie (PEL), Bristol-Myers Squibb (HPE, JG), Dagens Medisin (HPE), Eli Lilly (JG), HAI Interaktiv AS (HPE), MSD (JG), Novartis (HPE, JG), Pfizer (HPE, ESB, EAJ, SK), Pierre Fabre (HPE, JG, SK, PEL), Roche (HPE, BG, TA, PEL). Consulting or Advisory Role: AbbVie (VS), Aptitude Health (HPE), Astellas Oncology (BG), AstraZeneca (JG, PEL, JB), Daiichi Sankyo (HPE), Eli Lilly (HPE, JG), Laboratorios Farmaceuticos ROVI (PEL), MSD (HPE, JG), Novartis (HPE, JG), Pfizer (HPE, JB), Pierre Fabre (HPE), Roche (HPE, BG). Expert Testimony: Pfizer (HPE). Travel, Accommodations, Expenses: AstraZeneca (HPE, JB), Pierre Fabre (HPE, BG, PEL), Pfizer (JB), Roche (BG). Speakers' Bureau: Akademikonferens (PEL), Aptitude Health (PEL), AstraZeneca (JG), Bristol-Myers Squibb (JG), MSD (JG), Novartis (JG), Pfizer (JG), Pierre Fabre (JG). Patents, Royalties, Other Intellectual Property: Patent EP2389450 A1 (SK), Patent WO 2012/ 010661 (SK), Cytovation (PEL), PCT/EP2018/086759 (WO2019122411A1) (ALG, JB, VS). All remaining authors have declared no conflicts of interest. Data sharing Haukeland University Hospital and the University of Bergen support the dissemination of research data that has been generated, and increased cooperation between investigators. Trial data is collected, stored and disseminated according to institutional guidelines and in accordance with national laws and regulations to ensure the quality, integrity and use of clinical data. Study protocol, including plans for statistical analyses, is available online. Signed informed consent forms are stored at each participating hospital and are available for monitoring by regulatory authorities. After publication and upon formal request, raw data, including de-identified individual participant data and a data dictionary defining each field in the data set, will be shared according to institutional procedures. Requests are via a standard pro forma describing the nature of the proposed research and extent of data requirements. Data recipients are required to enter a formal data sharing agreement that describes the conditions for release and requirements for data transfer, storage, archiving, publication and intellectual property. Requests are reviewed by the PETREMAC study team in terms of scientific merit and ethical considerations, including patient consent. Data sharing is permitted if proposed projects have a sound scientific or patient benefit rationale, as agreed by the study team and with approval from the PETREMAC co-investigators as required.
Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.
Source: PubMed