High Detection Concordance Between Blood, Tumor for gBRCA1/2 Mutations in HER2– Metastatic Breast Cancer Observed

Germline testing for BRCA1/2 mutations in tumor tissue for treatment selection of PARP inhibition in HER2-negative metastatic breast cancer did not show large differences in outcomes compared with blood testing, inferring feasibility of tumor testing.

Patients with HER2-negative metastatic breast cancer who underwent germline testing to identify a BRCA1 or BRCA2mutations by both tumor tissue and blood testing revealed similar findings by both methods, according to a prespecified exploratory analysis of the phase 3 OlympiAD trial (NCT02000622) that was published in the Annals of Oncology.

Similarly, tumors response to olaparib (Lynparza) in this group were observed regardless of gene-specific loss of heterozygosity (gsLOH) status or homologous recombination deficiency (HRD) score, suggesting that additional tumor testing to guide PARP inhibitor treatment selection may not be supported.

“These final correlative analyses test the inferences that loss of a second allele and presence of genomic instability and reversion mutations affect sensitivity to olaparib,” wrote investigators of the study. “Low HRD score or lack of gsLOH did not preclude antitumor responses to olaparib in those with gBRCAm, although a potential impact on response rate to physician choice chemotherapy was seen.”

Of the 302 patients in this study, tumor tissue was available from 161 patients (53%) and BRCA mutation status is tumor tissue (tBRCAm) was available in 143 (47%). In total, 129 (43%) had an available HRD score and 125 (41%) had gsLOH data.

In all but one patient (142 out of 143), germline BRCA1/2 mutation by a blood test and tBRCAm were present, for a concordance of 99%. In 7 patients (6%) there was an absence of gsLOH, of whom a wild-type allele was retained in patients with a BRCA2 (8%) or BRCA1 (4%) mutations. Two out of 3 patients with a BRCA1 mutation and absence of gsLOH had a second mutation event that was too distant to confirm by raw sequences in transconfiguration.

A total of 21 patients (16%) had HRD negativity and more commonly harbored BRCA2 mutation and hormone receptor positivity. Patients with a BRCA2 mutation met the criteria for a low HRD score more frequently, at 27% (14 out of 51) vs 9% (7 out of 71%) with BRCA1. Hormone receptor–positive disease and a low HRD score was observed in 13 of 59 (22%) patients versus 8 of 70 (11%) with triple-negative disease.

Patients had a better overall response rate (ORR) with olaparib than with physician’s choice chemotherapy across HRD, tBRCAm, and hormone-receptor groups. Those with HRD scores of less than 42 and had an ORR of 60% (95% CI, 26.2%-87.8%) compared with 42 or greater at 57% (95% CI, 44.0%-69.2%).

In the 7 patients who had HRD scores of less than 42 and who received physician’s choice of chemotherapy, there were no responses vs an ORR of 29.4% in those with scores of 42 or more (95% CI, 10.3%-56.0%). One complete response was reported in a patient who lacked BRCA gsLOH, 2 patients had a partial response, and 1 had stable disease, and 1 had progressive disease.

Hazard ratios for progression-free survival (PFS) tended to favored the olaparib group compared with physician’s choice regardless of HRD score in patients assessed according to tBRCAm and hormone receptor status. The median PFS range was 6 months to not reached in the olaparib group and 1.5 months to 8.1 months in the physician’s choice group.


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. Ann Oncol. Published Online September 6, 2021. doi:10.1016/j.annonc.2021.08.2154