Analysis of mutation status and homologous recombination deficiency in tumors of patients with germline BRCA1 or BRCA2 mutations and metastatic breast cancer: OlympiAD

D Hodgson; Z Lai; S Dearden; J C Barrett; E A Harrington; K Timms; J Lanchbury; W Wu; A Allen; E Senkus; S M Domchek; M Robson

doi:10.1016/j.annonc.2021.08.2154

Analysis of mutation status and homologous recombination deficiency in tumors of patients with germline BRCA1 or BRCA2 mutations and metastatic breast cancer: OlympiAD

Ann Oncol. 2021 Dec;32(12):1582-1589. doi: 10.1016/j.annonc.2021.08.2154. Epub 2021 Sep 6.

Authors

D Hodgson¹, Z Lai², S Dearden³, J C Barrett², E A Harrington³, K Timms⁴, J Lanchbury⁴, W Wu⁵, A Allen⁵, E Senkus⁶, S M Domchek⁷, M Robson⁸

Affiliations

¹ AstraZeneca, Boston, USA. Electronic address: darren.hodgson@astrazeneca.com.
² AstraZeneca, Boston, USA.
³ AstraZeneca, Cambridge, UK.
⁴ Myriad Genetics, Salt Lake City, USA.
⁵ AstraZeneca, Gaithersburg, USA.
⁶ Medical University of Gdańsk, Gdańsk, Poland.
⁷ Basser Center, University of Pennsylvania, Philadelphia, USA.
⁸ Memorial Sloan Kettering Cancer Center, New York, USA.

PMID: 34500047
DOI: 10.1016/j.annonc.2021.08.2154

Abstract

Background: Presence of a germline BRCA1 and/or BRCA2 mutation (gBRCAm) may sensitize tumors to poly(ADP-ribose) polymerase (PARP) inhibition via inactivation of the second allele, resulting in gene-specific loss of heterozygosity (gsLOH) and homologous recombination deficiency (HRD). Here we explore whether tissue sample testing provides an additional route to germline testing to inform treatment selection for PARP inhibition.

Patients and methods: In this prespecified exploratory analysis, BRCA1 and/or BRCA2 mutations in blood samples (gBRCAm) and tumor tissue (tBRCAm) were analyzed from patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer and known gBRCAm, enrolled in the phase III OlympiAD trial. The frequency and nature of tBRCAm, HRD score status [HRD-positive (score ≥42) versus HRD-negative (score <42) using the Myriad myChoice® CDx test] and rates of gsLOH were determined, and their impact on clinical efficacy (objective response rate and progression-free survival) was explored.

Results: Tissue samples from 161/302 patients yielded tBRCAm, HRD and gsLOH data for 143 (47%), 129 (43%) and 125 (41%) patients, respectively. Concordance between gBRCAm and tBRCAm was 99%. gsLOH was observed in 118/125 (94%) patients [BRCA1m, 73/76 (96%); BRCA2m, 45/49 (92%)]. A second mutation event was recorded for two of the three BRCA1m patients without gsLOH. The incidence of HRD-negative was 16% (21/129) and was more common for BRCA2m (versus BRCA1m) and/or for hormone receptor-positive (versus triple-negative) disease. Olaparib antitumor activity was observed irrespective of HRD score.

Conclusions: gBRCAm identified in patients with HER2-negative metastatic breast cancer by germline testing in blood was also identified by tumor tissue testing. gsLOH was common, indicating a high rate of biallelic inactivation in metastatic breast cancer. Olaparib activity was seen regardless of gsLOH status or HRD score. Thus, additional tumor testing to inform PARP inhibitor treatment selection may not be supported for these patients.

Keywords: PARP inhibitor; gBRCAm; tumor tissue testing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

BRCA1 Protein / genetics
BRCA2 Protein / genetics
Breast Neoplasms* / drug therapy
Breast Neoplasms* / genetics
Female
Germ Cells
Germ-Line Mutation
Homologous Recombination
Humans
Mutation
Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use

Substances

BRCA1 Protein
BRCA1 protein, human
BRCA2 Protein
BRCA2 protein, human
Poly(ADP-ribose) Polymerase Inhibitors