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. 2018 Jan 3;18(1):16.
doi: 10.1186/s12885-017-3981-2.

Enhanced Response Rate to Pegylated Liposomal Doxorubicin in High Grade Serous Ovarian Carcinomas Harbouring BRCA1 and BRCA2 Aberrations

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Free PMC article

Enhanced Response Rate to Pegylated Liposomal Doxorubicin in High Grade Serous Ovarian Carcinomas Harbouring BRCA1 and BRCA2 Aberrations

Robert L Hollis et al. BMC Cancer. .
Free PMC article

Abstract

Background: Approximately 10-15% of ovarian carcinomas (OC) are attributed to inherited susceptibility, the majority of which are due to mutations in BRCA1 or BRCA2 (BRCA1/2). These patients display superior clinical outcome, including enhanced sensitivity to platinum-based chemotherapy. Here, we seek to investigate whether BRCA1/2 status influences the response rate to single-agent pegylated liposomal doxorubicin (PLD) in high grade serous (HGS) OC.

Methods: One hundred and forty-eight patients treated with single-agent PLD were identified retrospectively from the Edinburgh Ovarian Cancer Database. DNA was extracted from formalin-fixed paraffin-embedded (FFPE) archival tumour material and sequenced using the Ion Ampliseq BRCA1 and BRCA2 panel. A minimum variant allele frequency threshold was applied to correct for sequencing artefacts associated with formalin fixation.

Results: A superior response rate to PLD was observed in patients with HGS OC who harboured variants likely to affect BRCA1 or BRCA2 function compared to the BRCA1/2 wild-type population (36%, 9 of 25 patients versus 12.1%, 7 of 58 patients; p = 0.016). An enhanced response rate was also seen in patients harbouring only the BRCA1 SNP rs1799950, predicted to be detrimental to BRCA1 function (50%, 3 of 6 patients versus 12.1%, 7 of 58 patients; p = 0.044).

Conclusions: These data demonstrate that HGS OC patients with BRCA1/2 variants predicted damaging to protein function experience superior sensitivity to PLD, consistent with impaired DNA repair. Further characterisation of rs1799950 is now warranted in relation to chemosensitivity and susceptibility to developing ovarian carcinoma.

Keywords: BRCA1; BRCA2; Ovarian cancer; PLDH.

Conflict of interest statement

Ethics approval and consent to participate

Ethical approval for the use of tumour material was obtained from South East Scotland Human Annotated Bioresource (East of Scotland Research Ethics Service Reference 10/S1402/33). This approval was granted without the requirement for individual patient consent because patient follow-up data were gathered as part of routine care, and most patients included in the study were deceased.

Consent for publication

Not applicable.

Competing interests

MM has sat on advisory boards for Roche and delivered lectures for Boehringer Ingelheim. CG has sat on advisory boards for AstraZeneca, Nucana and Clovis and has delivered lectures for Roche and AstraZeneca. CG has also received research funding from AstraZeneca, Novartis and Aprea.

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Figures

Fig. 1
Fig. 1
Flow diagram of HGS OC patients evaluable for PLD response
Fig. 2
Fig. 2
a Comparison of bi-allelic SNV spectra between DNA extracted from FFPE and fresh frozen material in the TCGA data. b Proportions of previously documented variants retained (DVR) and novel variants removed (NVR) at various minimum allele frequency (AF) thresholds
Fig. 3
Fig. 3
Differential response rate to PLD chemotherapy according to BRCA1/2 status of sequenced tumour material. * indicates p < 0.05

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References

    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29. doi: 10.3322/caac.21254. - DOI - PubMed
    1. Pal T, Permuth-Wey J, Betts JA, Krischer JP, Fiorica J, Arango H, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807–2816. doi: 10.1002/cncr.21536. - DOI - PubMed
    1. Malander S, Rambech E, Kristoffersson U, Halvarsson B, Ridderheim M, Borg A, et al. The contribution of the hereditary nonpolyposis colorectal cancer syndrome to the development of ovarian cancer. Gynecol Oncol. 2006;101(2):238–243. doi: 10.1016/j.ygyno.2005.10.029. - DOI - PubMed
    1. Hollis RL, Gourley C. Genetic and molecular changes in ovarian cancer. Cancer Biol Med. 2016;13(2):236–247. doi: 10.20892/j.issn.2095-3941.2016.0024. - DOI - PMC - PubMed
    1. Walsh T, Casadei S, Lee MK, Pennil CC, Nord AS, Thornton AM, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011;108(44):18032–18037. doi: 10.1073/pnas.1115052108. - DOI - PMC - PubMed

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