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Prognostic impact of germline BRCA1/2 pathogenic variants in breast cancer

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Abstract

Purpose

This study investigates the impact of different subtypes of pathogenic BRCA variants on the prognosis and on the survival of breast cancer (BC) patients.

Methods

Associations between BRCA1/2 pathogenic variants (PVs) mutations, clinicopathological features, locoregional tumor reappearance, and survival data were analyzed. The Gray’s test was used to test difference of the cumulative incidence of local relapse between missense/splicing and other mutations, taking into of competing events. The multivariate proportional hazard model was used to assess the independent association between type of mutation and local relapse, after adjustment for other prognostic factors and clinicopathological characteristics.

Results

Out of 482 patients, 285 presented 98 different BRCA1 PVs and 201 harbored 103 different BRCA2 PVs. Missense mutations were found in 46 BC patients (9.5%), splicing mutations in 42 (8.6%), deletions in 206 (42.4%), insertions in 73 (15%), indel mutations in 6 (1.2%), nonsense mutations in 86 (17.7%), and large rearrangements in 27 (5.6%). Kalbfleisch and Prentice cumulative incidence curves analysis showed a significantly lower locoregional recurrence incidence in the missense/splicing group (Gray-test P-value = 0.011). We found that the risk of local relapse was 58% less likely in women carrying missense/splicing variants than in those with other PV subtypes (HR 95% CI 0.42 [0.21–0.82]; P-value = 0.0108). No significant differences were observed in overall survival (OS) in all groups.

Conclusions

Having been found to be associated with a lower risk of BC reappearance, germline BRCA1/2 PVs of the missense/splicing subtypes can be used as prognostic predictors and are likely to improve BC patients’ management.

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Data availability

Enquiries about data availability should be directed to the authors.

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Acknowledgements

This work was partially supported by the Italian Ministry of Health with Ricerca Corrente 5 × 1000 funds.

Funding

This study was supported by the IEO-MONZINO Foundation (Project title: “Prognostic impact of BRCA1/2 germline mutations in breast cancer mutant carriers” IEO833).

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Authors

Contributions

GC and MC contributed to conception and design. GC contributed to financial support. FM contributed to administrative support. AGG contributed to provision of study materials or patients. AGG, AG, and MM contributed to collection and assembly of data. SG and AG contributed to data analysis and interpretation. All authors contributed to manuscript writing and final approval of the manuscript.

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Correspondence to Giovanni Corso or Mariarosaria Calvello.

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The authors declare that they have no potential conflict of interests.

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The study was approved by the local ethic committee (Protocol nr. R781/81-IEO833).

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Corso, G., Girardi, A., Calvello, M. et al. Prognostic impact of germline BRCA1/2 pathogenic variants in breast cancer. Breast Cancer Res Treat 197, 103–112 (2023). https://doi.org/10.1007/s10549-022-06776-0

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  • DOI: https://doi.org/10.1007/s10549-022-06776-0

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