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Germline BRCA1/2 and Other Predisposition Genes in Patients With Metastatic Breast Cancer: Prevalence and Association With Prognosis


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In a German prospective registry study reported in the Journal of Clinical Oncology, Peter A. Fasching, MD, and colleagues identified the prevalence of germline mutations in BRCA1/2 and other breast cancer risk genes in patients with metastatic disease and found similar prognosis with presence vs absence of such mutations.

Peter A. Fasching, MD

Peter A. Fasching, MD

Study Details

Germline DNA from 2,595 patients with metastatic disease enrolled in the prospective PRAEGNANT registry was evaluated for mutations in 37 breast cancer predisposition genes, including BRCA1 and BRCA2. The frequencies of mutations in 12 established breast cancer risk genes—including BRCA1, BRCA2, ATM, BARD1, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, and TP53—were compared with findings in the Mayo Clinic Breast Cancer Study (MCBCS) prospective registry of patients with primary nonmetastatic breast cancer sequenced using the same QIAseq method. 

Key Findings

Among the 2,595 patients in the PRAEGNANT cohort, 425 mutations in any of the 37 genes were found in 396 patients (15.3%), with the most common being BRCA2 (2.9%), CHEK2 (2.2%), BRCA1 (2.0%), PALB2 (1.1%), and ATM (0.9%).

Germline mutations in the 12 established breast cancer predisposition genes, including BRCA1 and BRCA2, were found in 271 patients (10.4%), with a mutation in BRCA1 or BRCA2 in 129 (5.0%). A total of 76 (2.9%) had a mutation in other homologous recombination defect repair genes, 150 (5.8%) in other DNA repair genes, and 41 (1.6%) in other cancer risk genes.

BRCA1 mutation carriers had a higher frequency of brain metastasis (27.1%) compared with non-mutation carriers (12.8%).

Multigene panel testing may be considered in all patients with metastatic breast cancer because of the high frequency of germline mutations in BRCA1/2 and other breast cancer predisposition genes. Although the prognosis of mutation carriers and non-mutation carriers with metastatic breast cancer was similar, differences observed in tumor characteristics have implications for treatment and for future studies of targeted therapies.
— Peter A. Fasching, MD, and colleagues

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Mutations in the 12 established breast cancer risk genes were significantly more common in the PRAEGNANT cohort compared with patients with nonmetastatic breast cancer in the MCBCS cohort (10.4% vs 6.6%, P < .01). Germline mutations in BRCA2, PALB2, and TP53 were enriched in the PRAEGNANT cohort.

In the PRAEGNANT cohort, no difference between patients with BRCA1/2 and those with no mutations in any breast cancer risk genes was observed for progression-free survival (adjusted hazard ratio [HR] = 1.00, 95% confidence interval [CI] = 0.77–1.65) or overall survival (adjusted HR = 0.90, 95% CI = 0.61–1.35). Similarly, no differences in progression-free or overall survival were observed between patients with a mutation in any of the other categories of breast cancer risk genes vs those with no mutations in any risk genes.

The investigators concluded, “Multigene panel testing may be considered in all patients with metastatic breast cancer because of the high frequency of germline mutations in BRCA1/2 and other breast cancer predisposition genes. Although the prognosis of mutation carriers and non-mutation carriers with metastatic breast cancer was similar, differences observed in tumor characteristics have implications for treatment and for future studies of targeted therapies.”

Dr. Fasching, of University Hospital Erlangen and Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The PRAEGNANT network is supported by grants from Novartis, Celgene, and Pfizer. The Mayo Clinic Breast Cancer Study is supported by National Institutes of Health grants and the Breast Cancer Research Foundation. For full disclosures of the study authors, visit ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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