Olaparib monotherapy as primary treatment in unselected triple negative breast cancer.

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

PARP inhibitor homologous recombination deficiency neoadjuvant therapy olaparib prediction triple negative breast cancer

Journal

Annals of oncology : official journal of the European Society for Medical Oncology

ISSN: 1569-8041

Titre abrégé: Ann Oncol

Pays: England

ID NLM: 9007735

Informations de publication

Date de publication:
02 2021

Historique:

received: 30 04 2020

revised: 01 10 2020

accepted: 12 11 2020

pubmed: 27 11 2020

medline: 9 2 2021

entrez: 26 11 2020

Statut: ppublish

Résumé

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. 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. 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. Olaparib yielded a high clinical response rate in treatment-naïve TNBCs revealing HR deficiency, beyond germline HR mutations. ClinicalTrials.gov identifier: NCT02624973.

Sections du résumé

BACKGROUND

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.

Identifiants

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

pubmed: 33242536

pii: S0923-7534(20)43164-3

doi: 10.1016/j.annonc.2020.11.009

pii:

doi:

Substances chimiques

BRCA1 Protein 0

Phthalazines 0

Piperazines 0

Poly(ADP-ribose) Polymerase Inhibitors 0

olaparib WOH1JD9AR8

Banques de données

ClinicalTrials.gov

['NCT02624973']

Types de publication

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

Langues

eng

Sous-ensembles de citation

Pagination

240-249

Informations de copyright

Déclaration de conflit d'intérêts

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.