PMC8024449_01
Summary of genetic mutations showing the allele frequencies of cfDNA alterations in plasma across multiple time points.. ALK, anaplastic lymphoma receptor kinase gene; Amp, amplified by polymerase chain reaction; APC, adenomatous polyposis coli gene; ARID, AT-rich interactive domain gene; BRAF, B-Raf gene; BRCA2, breast cancer type 2 susceptibility gene; cfDNA, cell-free DNA; EGFR, epidermal growth factor receptor gene; ESR1, oestrogen receptor alpha gene; GATA3, GATA binding protein 3 gene; ND, not detected; RB1, retinoblastoma-1 gene.
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Plasma cell-free DNA (cfDNA) analysis (Guardant Health, Inc., Redwood City, CA, USA) confirmed the somatic BRCA2 H3154fs mutation (VAF, 15.3%; Figure 1). A cfDNA analysis at this time demonstrated undetectable levels of BRCA2 and of other mutations, including ESR1 and ALK (Figure 1). cfDNA analysis on 21 November 2018 showed co-occurring BRCA2 H3154fs (c.9460delC; VAF, 0.8%) and emerging K3151fs (c.9452_9453delAA; VAF, 0.4%) mutations (Figure 1).
CT scans of liver metastases. (a) January 2018, before olaparib therapy. (b) April 2018, following interruption to olaparib therapy. (c) June 2018, during olaparib therapy. (d) January 2019, after stopping olaparib therapy.. CT, computed tomography
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The capecitabine dosage was increased, and the cutaneous lesions responded briefly, but a CT scan in January 2018 showed multiple new liver lesions and doubling in size of the largest lesion (Figure 2). In April 2018, a CT scan showed liver lesion shrinkage of 80% (Figure 2).
Summary of BRCA2 genetic mutations showing the allele frequencies of cfDNA alterations in plasma from the analysis on 30 January 2019 and predicted net change in nucleotides highlighting predicted restoration of the open reading frame.. BRCA2, breast cancer type 2 susceptibility gene; cfDNA, cell-free DNA; Net  nt, net change in nucleotides; VAF, variant allele frequency.
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A subsequent cfDNA analysis (30 January 2019) showed VAF increases in the original BRCA2 H3154fs to 10.6% and in the recently emerging BRCA2 K3151fs to 4.2%, as well as three new genomically distinct variants of BRCA2 E3152fs (c.9453dupA, c.9450_9454delAAAAGinsCAAAAA, and c.9455_9456delAG) at 1.4%, 1.2% and 1.1% VAF, respectively, and three genomically distinct BRCA2 Q3156fs variants (c.9465dupT, c.9471_9472insT, and c.9466delCinsAA), at 0.5%, 0.4%, and 0.2% VAF, respectively (Figure 3).