Findings from a prespecified exploratory analysis of the OlympiAD study (NCT02000622), in patients with HER2-negative metastatic breast cancer (MBC) and already confirmed germline BRCA mutations, suggest that there is no clear benefit of additional tumor testing for the homologous recombination deficiency (HRD) score or detection of gene-specific loss of heterozygosity (LOH) to determine if they are likely to respond to the treatment with a poly(ADP-ribose) polymerase (PARP) inhibitor.[1]

The results of the study’s analysis demonstrated that tumor testing was able to detect known germline BRCA mutations with 99% concordance for tumor tissue and blood. HRD scores were mostly high and gene-specific LOH was >90%.

Olaparib (Lynparza®; AstraZeneca) activity was seen in few tumors with low HRD scores or lacking LOH. Additional measurement of genome instability and gene-specific LOH may not inform the selection of treatment with PARP inhibitor according to the study team who published the findings of the analysis online on September 5, 2021, in Annals of Oncology.

The study’s authors wrote that in the phase III OlympiAD study, treatment with olaparib conferred a significant benefit in progression-free survival (PFS) compared with physician’s choice of single-agent chemotherapy in patients with HER2-negative metastatic breast cancer and germline BRCA mutations. This benefit was consistent across patients with hormone receptor (HR)-positive and triple-negative disease, and across those with BRCA1 and BRCA2 mutated tumors.

The overall aim of this prespecified exploratory analysis was to understand better how PARP inhibitors target deficiencies in the homologous recombination repair pathway. Specifically, this analysis explored whether tissue sample testing provides an additional route for treatment selection to germline testing by assessing the ability of tumor tissue testing to detect known germline BRCA mutations, assessing rates of gene-specific LOH, determining HRD scores, and assessing whether the absence of gene-specific LOH or low HRD scores impact efficacy of olaparib.

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In particular, the researchers determined the frequency and nature of BRCA mutations in tumor tissue, HRD score status where HRD-positive was defined if the score was ≥42 versus <42 in case of HRD-negative score by using the Myriad myChoice® CDx test; they also determined rates of gene-specific LOH and their impact on objective response rate and PFS.

Tissue samples from 161 of 302 patients yielded BRCA mutations in tumor tissue, HRD and gene-specific LOH data for 143, 129 and 125 patients, respectively. Concordance between germline BRCA mutations and tumor tissue BRCA mutations was 99%. Gene-specific LOH was observed in 118 of 125 (94%) patients; 73 of 76 (96%) in case of BRCA1 mutations, 45 of 49 (92%) in case of BRCA2 mutations. A second mutation event was recorded in 2 of 3 patients with BRCA1 mutations without gene-specific LOH. The HRD-negative incidence was 16% and was more common for BRCA2 mutations versus BRCA1 mutations and/or for HR-positive versus triple-negative disease. Olaparib activity was observed irrespective of HRD score.

The authors reported several limitations of their study. The population for this analysis was selected in a non-random way from the intent-to-treat population, so that comparison between treatment arms may be confounded by baseline factors. Many samples originated from primary, rather than metastatic tumor sites. Intratumoral genetic heterogeneity exists in breast tumors and a single biopsy specimen may not be representative of the entire lesion.

The authors concluded that germline BRCA mutations identified in patients with HER2-negative metastatic breast cancer by germline testing in blood was also identified by tumor tissue testing. Gene-specific LOH was common, indicating a high rate of biallelic inactivation in metastatic breast cancer. The activity of olaparib was observed regardless of gene-specific LOH status or HRD score. Therefore, additional tumor testing to inform the selection of treatment with PARP inhibitor may not be supported for these patients.

Future studies
The authors commented that further studies will elucidate the molecular mechanisms underlying resistance to PARP inhibition in metastatic breast cancer with BRCA mutations and whether patients with HRD-positive, BRCA wild-type tumors can benefit from treatment with olaparib.

This work was funded by AstraZeneca and is part of an alliance between AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ (MSD).

Clinical Trials
Assessment of the Efficacy and Safety of Olaparib Monotherapy Versus Physicians Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients With Germline BRCA1/2 Mutations. (OlympiAD) – (NCT02000622),

Highlights of Prescription information
Olaparib (Lynparza®; AstraZeneca) [Prescription Information]

[1] Hodgson D, Lai Z, Dearden S, et al. Analysis of mutation status and homologous recombination deficiency in tumors of patients with germline BRCA1 or BRCA2 mutations and metastatic breast cancer: OlympiAD. Annals of Oncology; Published online 5 September 2021. DOI: [Article]

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