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Case Reports
. 2023 Sep 25;17(1):407.
doi: 10.1186/s13256-023-04139-x.

Metastatic lung adenocarcinoma with BRCA2 mutation and longstanding disease control on olaparib, developing triple negative breast adenocarcinoma with additional BRCA2 reversion mutation: a case report

Auro Del Giglio  1 , Beatriz da Costa Aguiar Alves  2 , André Márcio Murad  3 , Fernando Luiz Affonso Fonseca  2   4
Affiliations
Case Reports

Metastatic lung adenocarcinoma with BRCA2 mutation and longstanding disease control on olaparib, developing triple negative breast adenocarcinoma with additional BRCA2 reversion mutation: a case report

Auro Del Giglio et al. J Med Case Rep. .

Abstract

Background: The BRCA2 gene is a well-known tumor suppressor gene implicated in breast and ovarian cancers. BRCA1/2 mutations can be sensitive to poly ADP-ribose polymerase (PARP) inhibitors such as olaparib. However, some of these patients develop resistance to this treatment and an essential factor contributing to acquired insensitivity is the occurrence of reversion mutations in the BRCA1/2 genes.

Case presentation: We report the case of a 65-year-old Brazilian female patient who had previously been diagnosed with metastatic lung carcinoma carrying a BRCA2 mutation that had extended to the central nervous system. Following disease progression, olaparib was administered, resulting in a stabilizing effect on her condition for ~ 30 months. During a routine follow-up, a new triple-negative breast tumor was found. Genetic testing revealed the presence of two distinct BRCA2 gene mutations in the breast tumor. The original mutation (p.Val220Ilefs4) led to a frameshift, culminating in the production of a truncated and non-functional BRCA2 protein; the second mutation, K437fs22, rectified the reading frame of exon 11. Consequently, Rad51 could properly bind to BRCA2-an essential protein crucial for DNA repair. This restoration resulted in a functional BRCA2 protein, effectively elucidating the clinical resistance observed in the new breast tumor in this case.

Conclusions: This case report highlights the clinical significance of comprehensive next-generation sequencing analyses for lung adenocarcinomas, both at diagnosis and upon progression. Such analyses enable informed decisions regarding targeted therapies and facilitate a deeper comprehension of resistance mechanisms.

Keywords: BRCA2; Reversion mutation; Therapy resistance.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
A Upper three images: Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT) scan results before starting olaparib in October 2020. Lower three images of December 2020 after 1 month of olaparib showing a partial response in the mediastinal and lung nodules. B FDG PET/CT scan from February 2023 at the level of the right breast showing the appearance of a new hypermetabolic nodule in the right breast and no activity in previous lung and mediastinal nodules
Fig. 2
Fig. 2
Graphical representation of BRCA2 gene structure and localization of p.Val220Ilefs*4 and K437fs*22 mutations (exons 8 and 10, respectively) and domains
See this image and copyright information in PMC

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