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

doi:10.1016/j.annonc.2020.11.009

Olaparib monotherapy as primary treatment in unselected triple negative breast cancer

Ann Oncol. 2021 Feb;32(2):240-249. doi: 10.1016/j.annonc.2020.11.009. Epub 2020 Nov 24.

Authors

H P Eikesdal¹, S Yndestad², A Elzawahry², A Llop-Guevara³, B Gilje⁴, E S Blix⁵, H Espelid⁶, S Lundgren⁷, J Geisler⁸, G Vagstad⁹, A Venizelos², L Minsaas², B Leirvaag², E G Gudlaugsson¹⁰, O K Vintermyr¹¹, H S Aase¹², T Aas¹³, J Balmaña³, V Serra³, E A M Janssen¹⁰, S Knappskog², P E Lønning²

Affiliations

¹ Department of Oncology, Haukeland University Hospital, Bergen, Norway; K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway. Electronic address: hans.eikesdal@uib.no.
² Department of Oncology, Haukeland University Hospital, Bergen, Norway; K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.
³ Vall d'Hebron Institute of Oncology, Barcelona, Spain.
⁴ Department of Hematology and Oncology, Stavanger University Hospital, Stavanger, Norway.
⁵ Immunology Research Group, Institute of Medical Biology, UiT The Arctic University of Norway, Tromsø, Norway; Department of Oncology, University Hospital of North Norway, Tromsø, Norway.
⁶ Department of Surgery, Haugesund Hospital, Haugesund, Norway.
⁷ Cancer Clinic, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
⁸ Department of Oncology, Akershus University Hospital, Lørenskog, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁹ Department of Oncology, Førde Hospital, Førde, Norway.
¹⁰ Department of Pathology, Stavanger University Hospital, Stavanger, Norway.
¹¹ Department of Pathology, Haukeland University Hospital, Bergen, Norway; The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
¹² Department of Radiology, Haukeland University Hospital, Bergen, Norway.
¹³ Department of Surgery, Haukeland University Hospital, Bergen, Norway.

PMID: 33242536
DOI: 10.1016/j.annonc.2020.11.009

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.

Publication types

Clinical Trial, Phase II
Research Support, Non-U.S. Gov't

MeSH terms

BRCA1 Protein / genetics
Humans
Phthalazines / therapeutic use
Piperazines / therapeutic use
Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
Triple Negative Breast Neoplasms* / drug therapy
Triple Negative Breast Neoplasms* / genetics

Substances

BRCA1 Protein
Phthalazines
Piperazines
Poly(ADP-ribose) Polymerase Inhibitors
olaparib

Associated data

ClinicalTrials.gov/NCT02624973