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No Benefit of Additional Tumour Testing in HER2-negative Metastatic Breast Cancer with Already Confirmed Germline BRCA Mutations

September 9, 2021

According to findings from a prespecified exploratory analysis of the OlympiAD study, in patients with HER2-negative metastatic breast cancer and already confirmed germline BRCA mutations, there is no clear benefit of additional tumour 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 PARP inhibitor. Tumour testing was able to detect known germline BRCA mutations with 99% concordance for tumour tissue and blood. HRD scores were mostly high and gene-specific LOH was >90%. Olaparib activity was seen in few tumours with low HRD scores or lacking LOH. Additional measurement of genome instability and gene-specific LOH may not inform selection of treatment with PARP inhibitor according to the study team who published the findings on 5 September 2021 in the Annals of Oncology.

The authors wrote in the study background 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 tumours.

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 tumour 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.

In particular, the researchers determined the frequency and nature of BRCA mutations in tumour 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 tumour tissue, HRD and gene-specific LOH data for 143, 129 and 125 patients, respectively. Concordance between germline BRCA mutations and tumour 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 tumour sites. Intratumoural genetic heterogeneity exists in breast tumours 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 tumour tissue testing. Gene-specific LOH was common, indicating a high rate of biallelic inactivation in metastatic breast cancer. Activity of olaparib was observed regardless of gene-specific LOH status or HRD score. Therefore, additional tumour testing to inform selection of treatment with PARP inhibitor may not be supported for these patients.

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 tumours 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).