Cancer Res Treat.  2023 Jul;55(3):1048-1052. 10.4143/crt.2022.1529.

Efficacy of Olaparib in Treatment-Refractory, Metastatic Breast Cancer with Uncommon Somatic BRCA Mutations Detected in Circulating Tumor DNA

• Yoon JK
• Ahn J
• Kim S
• Kim HP
• Kang Jk
• Bang D
• Lim Y
• Kim TY

• KMID: 2544184
• DOI: http://doi.org/10.4143/crt.2022.1529

Abstract

Poly(ADP-ribose) polymerase inhibitors have been shown dramatic responses in patients with BRCAness. However, clinical studies have been limited to breast cancer patients with germline mutations. Here, we describe a patient with metastatic breast cancer who had a rare BRCA1 somatic mutation (BRCA1 c.4336G>T (p.E1446*)) detected by cell-free DNA analysis after failing standard therapies. This tier III variant of unknown significance was predicted to be a pathogenic variant in our assessment, leading us to consider off-label treatment with olaparib. The patient responded well to olaparib for several months, with a decrease in allele frequency of this BRCA1 somatic mutation in cell-free DNA. Olaparib resistance subsequently developed with an increase in the allele frequency and new BRCA1 reversion mutations. To our knowledge, this is the first report confirming BRCA1 c.4336G>T (p.E1446*) as a mutation sensitive to olaparib in breast cancer and describing the dynamic changes in the associated mutations using liquid biopsy.

Keyword

Breast neoplasms; Cell-free nucleic acids; Liquid biopsy; Precision medicine

Figure

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  Fig. 1 Circulating tumor DNA (ctDNA) analysis and the response to ctDNA-based therapy. (A) Temporal changes of cancer antigen 15-3 (CA 15-3) levels and variant allele frequencies of BRCA1 p.E1446* with ctDNA tumor response map. (B, C) Computed tomography (CT) scans before and during olaparib treatment showed significant shrinkage of the liver and lung nodules (red arrows) during treatment. (D) A follow-up CT scan showed increasing size of the liver and lung nodules (red arrows) and the presence of a new left pleural effusion (blue arrow). PD, progression of disease; PR, partial response; VAF, variant allele frequency.

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  Fig. 2 Primary and reversion BRCA1 mutations detected in this patient. (A) Functional domain annotation of mutations. (B) DNA and corresponding amino acid sequence changes of mutations, with allele frequencies, in April 2022. BRCT, BRCA1 C-terminal; NLS, nuclear localization signal.

Reference

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