Lilla Reiniger1,2, Miklos Diossy3, Zsofia Sztupinszki3,4, Marcin Krzystanek3, Kirsten M. Timms5, Chris Neff5, Cara Solimeno5, Dmitry Pruss5, Aron C. Eklund3, Erika Tóth6, Orsolya Kiss6, Orsolya Rusz7, Gábor Cserni7,8, Tamás Zombori7, Borbála Székely9,10, József Tímár9, István Csabai11, Zoltán Szállási2,3,12
1 1st Department of Pathology and Experimental Research, Semmelweis University, Budapest
2 2nd Department of Pathology, MTA-SE NAP, Brain Metastasis Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest
3 Department of Bio and Health Informatics, Technical University of Denmark, Lyngby
4 2nd Department of Pediatrics, Semmelweis University, Budapest
5 Myriad Genetics Inc, Salt Lake City
6 Department of Pathology, National Institute of Oncology, Budapest
7 Department of Oncotherapy, University of Szeged, Szeged
8 Department of Pathology, Bács-Kiskun County Teaching Hospital, Kecskemét
9 2nd Department of Pathology, Semmelweis University, Budapest
10 Department of Oncological Internal Medicine and Clinical Pharmacology "B", National Institute of Oncology, Budapest
11 Department of Physics of Complex Systems, Eötvös Loránd University, Budapest
12 Computational Health Informatics Program, Boston Children’s Hospital, USA, Harvard Medical School, Boston
In a recent study Brastianos et al. performed whole exome sequencing of primary tumours and corresponding brain metastases. Using their data, we determined the homologous recombination deficiency (HRD) score for each breast cancer related samples. HRD score is important in predicting response to treatments: low HRD scores are associated with less/no response to PARP-inhibitors and platinum-based therapy. We found that HRD scores for the brain metastases tended to be higher than their paired primary tumours. This suggests that HR deficiency can develop in brain metastasis regardless of the HRD status of the primary breast carcinoma.
The aim of this study was to confirm our results gained by the in silico data analysis on an independent validation cohort.
The HRD status of 17 cases of primary breast cancer and corresponding brain metastases were determined by our collaborator Myriad Genetics. DNA was extracted from formalin-fixed paraffin-embedded tissues. Targeted sequencing of a panel of 111 genes was carried out on an Illumina HiSeq2500 sequencer. HRD scores were calculated; and HR deficiency was defined as high HRD score and/or mutated tumour BRCA1/2. HR nondeficiency was defined as low HRD score and nonmutated tumour BRCA1/2.
In most of the cases the HRD score was higher in the brain metastasis compared to the primary breast carcinoma (p<0.001). The HRD status of the brain metastasis changed in 4 cases compared to the primary tumour. The HRD status became positive in 3 of these cases, suggesting that homologous recombination deficiency developed in these brain metastases.
In this study we confirmed our previous observation that HR deficiency may develop in a brain metastasis regardless of the HRD status of the primary breast carcinoma. This may have an important impact on therapeutic strategic decisions: even if the primary tumour seems to be PARP-inhibitor resistant, the brain metastases could still become sensitive.
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