Poly(ADP-ribose) polymerase inhibitors (PARPis), such as olaparib and talazoparib, are approved for treating HER2-negative metastatic breast cancer with deleterious germline BRCA mutations. Their efficacy in breast cancers with somatic BRCA mutations remains less established, with most clinical trials focusing on germline mutations. While some research suggests PARPis might be effective against somatic BRCA1/2 mutations, evidence is scarce, particularly for rare mutations of uncertain clinical significance. This case study investigates the efficacy of olaparib in a patient with metastatic breast cancer carrying the rare somatic BRCA1 c.4336G>T (p.E1446*) mutation, a tier III variant of unknown significance. The study utilized serial circulating tumor DNA (ctDNA) analysis via liquid biopsy to monitor the patient's response to olaparib and detect the emergence of resistance. The primary aim is to evaluate the clinical response to olaparib in this context and to characterize the dynamic mutational changes in the ctDNA throughout the treatment course, potentially revealing mechanisms of acquired resistance.

Existing literature supports the efficacy of PARPis in patients with germline BRCA mutations in metastatic breast cancer. Clinical trials like those evaluating olaparib (Robson et al., 2017) and talazoparib (Litton et al., 2018) have established their benefit in this population. However, data regarding the efficacy of PARPis in patients with somatic BRCA mutations is limited. Studies like the TBCRC 048 phase II trial (Tung et al., 2020) have explored olaparib in metastatic breast cancer patients with mutations in homologous recombination-related genes, including somatic BRCA mutations, but the data is less conclusive for rare variants. The mutational landscape of metastatic cancers is complex (Zehir et al., 2017), underscoring the need for further research into the efficacy of targeted therapies for specific somatic mutations. Prior studies have also shown that BRCA reversion mutations can be a mechanism of acquired PARPi resistance in other cancers, particularly in ovarian cancer (Lin et al., 2019; Li et al., 2020).

This is a case report detailing the clinical course and molecular analysis of a single patient. A 48-year-old woman with metastatic breast cancer who had progressed through multiple lines of therapy underwent genomic profiling using plasma ctDNA analysis. Peripheral blood samples were collected, and cfDNA was extracted using a Maxwell RSC cfDNA Plasma Kit (Promega). Next-generation sequencing (NGS) was performed using an AlphaLiquid 100 target capture panel (IMBdx) and the IMBdx NGS Library Prep Kit (IMBdx) on an Illumina NovaSeq 6000 platform. Bioinformatics analysis was conducted using an in-house algorithm to identify mutations. The patient's response to olaparib treatment was assessed through clinical imaging (CT scans), serum CA 15-3 levels, and serial ctDNA analysis to monitor the allele frequency of the BRCA1 mutation and the emergence of potential resistance mutations. The bioinformatic tools used included CADD for assessing the deleteriousness of the BRCA1 variant and an in-house homologous recombination repair deleteriousness (HRD) score.

ctDNA analysis revealed a rare somatic BRCA1 mutation (c.4336G>T, p.E1446*) with an initial allele frequency of 6.68%. The mutation was predicted to be pathogenic using CADD (C-score of 34) and the in-house HRD score (0.87). Olaparib treatment resulted in a partial response, with a 55% decrease in the sum of target lesions and a reduction in the BRCA1 mutation allele frequency to 0.25%. After 8 months, however, disease progressed, with an increase in lesion size and new lesions. The BRCA1 mutation allele frequency increased to 19.16%, accompanied by the emergence of new BRCA1 reversion mutations (p.E1446L, p.E1446Y, p.S1436_S1448del, and p.E1446Q) at or near the original mutation site. These reversion mutations restored portions of the truncated BRCA1 protein. A concurrent increase in the allele frequency of a somatic ESR1 mutation (c.1607T>A, p.L536H) from 0.05% to 5.95% was also observed, which is associated with resistance to aromatase inhibitors. This suggests that the reversion mutations in BRCA1 and the ESR1 mutation may have contributed to the development of olaparib resistance.

This case demonstrates the potential of olaparib for treating metastatic breast cancer with rare somatic BRCA mutations. The initial response to olaparib supports the clinical utility of PARPis even in patients with uncommon mutations that are initially classified as variants of uncertain significance. The use of ctDNA analysis via liquid biopsy proved crucial for monitoring treatment response and identifying the mechanism of acquired resistance. The emergence of BRCA1 reversion mutations emphasizes the importance of considering such mechanisms when treating patients with PARPis. The concurrent emergence of the ESR1 mutation highlights the complexity of resistance mechanisms and the potential for multiple factors contributing to treatment failure.

This case report highlights the clinical benefit of olaparib in a patient with metastatic breast cancer and a rare somatic BRCA1 mutation, initially classified as a variant of uncertain significance. The use of liquid biopsy for monitoring treatment response and detecting resistance mechanisms, such as BRCA1 reversion mutations, is essential. Further research is needed to better understand the prevalence and clinical implications of such rare somatic BRCA mutations and to develop strategies for overcoming PARPi resistance. The findings underscore the growing importance of precision medicine approaches in treating advanced cancers.

This study is limited by its single-patient design, limiting generalizability of the findings. The in-house HRD score used for assessing the deleteriousness of the mutation lacks external validation. Furthermore, the exact contribution of each identified mutation to olaparib resistance remains unclear, and other unidentified factors may have contributed to the development of resistance. This is a single case and additional case reports are needed to confirm the findings.