Steven Sorscher
A germline (gl) pathogenic BRCA alteration or mutation is the molecular basis for diagnosing an individual with Hereditary Breast and Ovarian Cancer (HBOC) syndrome, the most common inherited breast cancer-predisposing syndrome. The gatekeeper or transforming event almost always involves BRCA Loss of Heterozygosity (LOH), which results in loss of expression of normal BRCA protein. Recently, the Federal Drug Administration (FDA) approved PARP inhibitor therapy for patients harboring a gl BRCA alteration who have metastatic breast cancer based on a 59.9% response rate of these tumors to PARP inhibitor therapy. Here, a patient with a gl BRCA pathogenic alteration whose metastatic breast cancer responded to PARP inhibitor therapy is described. However, next-generation sequencing (NGS) liquid biopsy (cell-free (cf) DNA demonstrated no apparent BRCA LOH (the molecular hallmark of BRCA-related breast cancers) and therefore the response of her tumor to the PARP inhibitor would be unexpected. PARP inhibitor therapy would be expected to be effective only if the tumor lacked normal BRCA protein expression, as is seen with BRCA LOH in tumor-derived DNA. The challenges involved in confirming BRCA LOH based on mutant allelic frequency (MAF) in the cf DNA NGS assay are discussed as well as possible explanations for the demonstrated radiographic response to the PARP inhibitor, despite the apparent lack of BRCA LOH.
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