Page 146 - SRPSKO DRUŠTVO ISTRAŽIVAČA RAKA

Serbian Association for Cancer Research SDIRSACR

Ministry of Science, Technological Development and Innovation of the Republic of Serbia (agreement no.
451-03-66/2024-03/200110).

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Germline BRCA1 and BRCA2 Testing in the Context of Personalized Therapy: National Experience from
Serbia in Breast Cancer Management

Valentina Karadžić1, Marija Đorđić Crnogorac1, Slavica Šolajić2, Dimitar Jakimov2, Vesna Kojić2, Lidija Aleksić2, Nataša
Tošić3, Bojan Ristivojević3, Ivana Grubiša3, Marina Jelovac3, Đorđe Stojanović3, Branka Zukić3, Tatjana Ivković Kapicl2,
Ana Krivokuća1

1Genetic Counseling Department, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia
2Department of Pathoanatomical Diagnostics, Oncology Institute of Vojvodina, Sremska Kamenica, Serbia
3Group for Molecular Biomedicine, Institute of Molecular Genetics and Genetic Engineering, Belgrade, Serbia

Keywords: BRCA1, BRCA2, NGS, Breast Cancer, Olaparib

Background: Breast cancer is the most common cancer in women, and germline BRCA1/2 mutations significantly
increase lifetime risk, guiding both risk assessment and treatment. PARP inhibitors, like olaparib, exploit defective
DNA repair in BRCA-mutated cells, improving progression-free survival in HER2-negative patients. This study aimed to
implement nationwide BRCA testing in Serbia, enabling personalized therapy for eligible patients. It also marked the
first collaborative effort of the three major Serbian institutions to introduce a unified NGS protocol for BRCA testing.
Patients and Methods: From April 2024 to June 2025, a total of 1,739 patients were tested across three institutions:
Institute for Oncology and Radiology of Serbia, Oncology Institute of Vojvodina, and Institute of Molecular Genetics
and Genetic Engineering. BRCA1/2 mutation analysis was performed using next-generation sequencing on the Illumina
platform with the Devyser BRCA NGS kit. Genomic DNA extracted from peripheral blood was quality-controlled and
subjected to massive parallel sequencing. Data analysis was conducted using Amplicon Suite software.
Results: Most patients (72.5%) underwent testing at an early stage of disease. HR+/HER2− breast cancer was the
predominant subtype (63.7%). Pathogenic or likely pathogenic variants were detected in 97 patients (5.6%), including
56 BRCA1 (3.2%) and 41 BRCA2 (2.4%) mutations. Variants of uncertain significance were identified in 42 cases (2.4%).
Among BRCA1-positive patients, 76.8% presented with triple-negative breast cancer (age range: 32–70 years; mean
age: 50 years). In contrast, BRCA2-positive cases were predominantly HR+/HER2− (65.8%; age range: 34–78 years;
mean age: 53.5 years). A notable variation in the geographical distribution of BRCA1/2 mutations was observed, with
prevalence rates of 3.2% in southern Serbia, 5.0% in central Serbia, and 8.35% in Vojvodina.
Conclusions: The introduction of olaparib for breast cancer treatment in Serbia strengthens precision oncology
by offering an additional targeted therapy. Nationwide collaboration among major institutions has enabled the
implementation of germline BRCA testing, which is crucial for identifying patients eligible for PARP inhibitors and
for bringing personalized medicine into routine clinical care. Ongoing research should assess real-world outcomes in
patients treated with olaparib, while this germline testing will also provide valuable insights into the genetic landscape
of the Serbian population.

Acknowledgments and funding: We acknowledge AstraZeneca for donating the BRCA tests used in this nationwide
testing. The study was designed, initiated, and conducted independently by Institute for Oncology and Radiology
of Serbia, Oncology Institute of Vojvodina, and Institute of Molecular Genetics and Genetic Engineering without
sponsorship or involvement from AstraZeneca.

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