Identification of Prognostic Groups in High-Grade Serous Ovarian Cancer Treated with Platinum–Taxane Chemotherapy

Chen, Ping; Huhtinen, Kaisa; Kaipio, Katja; Mikkonen, Piia; Aittomäki, Viljami; Lindell, Rony; Hynninen, Johanna; Auranen, Annika; Grénman, Seija; Lehtonen, Rainer; Carpén, Olli; Hautaniemi, Sampsa

doi:10.1158/0008-5472.can-14-3242

Cited by 35 publications

(30 citation statements)

References 47 publications

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“…Moreover, the BRCA result was considered useful in management planning of 79% of patients with active disease: 97% of patients with a mutation and 75% of patients without a mutation. This is consistent with increasing data showing that stratification of ovarian cancer by BRCA status can provide important clinical, therapeutic and prognostic information, and should be part of standard care 7,8,10 .…”

Section: Discussionsupporting

confidence: 90%

“…Approximately 10-15% of ovarian cancer is due to germline mutations in BRCA1 or BRCA2 (collectively termed 'BRCA'), rising to 15-20% of non-mucinous ovarian cancer [2][3][4][5][6] . Determining the BRCA status of ovarian cancer patients has important therapeutic and prognostic implications [7][8][9][10] . Additionally, it provides improved cancer risk information for family members and opportunities for predictive gene testing and risk-reducing interventions.…”

Section: Introductionmentioning

confidence: 99%

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Implementing rapid, robust, cost-effective, patient-centred, routine genetic testing in ovarian cancer patients

George

Riddell²,

Seal

et al. 2016

Preprint

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SUMMARYBackground:Advances in DNA sequencing have made gene testing fast and affordable, but adaptation of clinical services to capitalise on this for patient benefit has been slow. Ovarian cancer exemplifies limitations of current systems and potential benefits of increased gene testing. Approximately 15% of ovarian cancer patients have a germline mutation in BRCA1 or BRCA2 (collectively termed ‘BRCA’) and this has substantial implications for their personal management and that of their relatives. However, in most countries implementation of BRCA testing in ovarian cancer has been inconsistent and largely unsuccessful.Methods:We developed a mainstream pathway in which BRCA testing was undertaken by cancer team members after 30 minutes online training. Patients with a mutation were sent a genetic appointment with their results. Cascade testing to relatives was performed via standard clinical genetic procedures.Findings:207 women with ovarian cancer were offered gene testing through the mainstream pathway and all accepted. 33 (16%) had a BRCA mutation. The result informed management of 79% (121/154) women with active disease including 97% (32/33) women with a mutation. All mutation-positive women and ~3.5 relatives per family have been seen in genetics. Patient and clinician feedback was very positive. >95% found the pathway to be simple and effective. The pathway offers considerable reduction in time (~5-fold) and resource requirements (~13-fold) compared to the traditional genetic pathway. We estimate it would deliver £2.6M NHS cost savings per year, and would allow implementation of national testing recommendations with existing infrastructure.Interpretation:Mainstream genetic testing is effective, efficient and patient-centred and offers a mechanism for large-scale implementation of BRCA gene testing in cancer patients. The principles could be applied in many other countries and to many other areas of genomic medicine.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Implementing rapid, robust, cost-effective, patient-centred, routine genetic testing in ovarian cancer patients

George

Riddell²,

Seal

et al. 2016

Preprint

View full text Add to dashboard Cite

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“…Evidence exists that ovarian cancer patients carrying germline BRCA mutations have an improved prognosis in comparison to sporadic cases [9–11]. BRCA-associated ovarian carcinomas are more aggressive but show higher susceptibility to platinum-salts and other DNA-damaging agents [10–15].…”

Section: Discussionmentioning

confidence: 99%

Treatment related toxicity in BRCA1-associated epithelial ovarian cancer – is DNA repairing impairment associated with more adverse events?

Badora-Rybicka

Budryk

Nowara

et al. 2016

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Aim of the studyThe presence of BRCA germline mutations in patients with ovarian cancer has been shown to have predictive and prognostic significance, including increased platinum-sensitivity. The aim of the study was to evaluate if patients with BRCA1-associated ovarian cancer have more treatment related adverse events and, if so, does it have impact on chemotherapy outcomes.Material and methodsWe conducted a retrospective analysis of medical records of 172 patients with newly diagnosed epithelial ovarian cancer, treated in Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch between 2007 and 2013. Ninety-six of these patients have known BRCA mutation status – 21 patients were BRCA1(+) and 75 BRCA1(–). Analysed treatment related adverse events (AE’s) were: haematological toxicity, nausea/vomiting, neuropathy and mucositis.ResultsGrade 3–4 haematological AE’s were significantly more common among BRCA1(+) patients (OR = 3.86; 95% CI: 1.14–13.23; p = 0.02). There was no association between BRCA1 mutation status and neuropathy (p = 0.73) or nausea/vomiting (p = 0.91). Occurrence of above mentioned AE’s has no significant association with PFS (p = 0.75, 0.64, 0.97 respectively) and OS (p = 0.64, 0.69, 0.73 respectively).ConclusionsAmong patients with BRCA1-associated epithelial ovarian cancer we observed significantly more grade 3–4 haematological complications after chemotherapy. However, occurrence of AE’s did not correlate with better outcomes in this subgroup.

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“…Expression was determined in triplicate samples using TaqMan qRT-PCR with Applied Biosystems 7900HT instrument. Raw qRT-PCR Ct values were normalized against the geometric mean of PPIA and TBP 17 .…”

Section: Methodsmentioning

confidence: 99%

DNA methylation and Transcriptome Changes Associated with Cisplatin Resistance in Ovarian Cancer

Lund

Huhtinen

Salmi

et al. 2017

Sci Rep

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High-grade serous ovarian cancer is the most common ovarian cancer type. Although the combination of surgery and platinum-taxane chemotherapy provide an effective treatment, drug resistance frequently occurs leading to poor outcome. In order to clarify the molecular mechanisms of drug resistance, the DNA methylation and transcriptomic changes, associated with the development of drug resistance in high-grade serous ovarian cancer, were examined from patient derived malignant ascites cells. In parallel with large-scale transcriptome changes, cisplatin resistance was associated with loss of hypermethylation at several CpG sites primarily localized in the intergenic regions of the genome. The transcriptome and CpG methylome changes in response to cisplatin treatment of both sensitive and resistant cells were minimal, indicating the importance of post-translational mechanisms in regulating death or survival of the cells. The response of resistant cells to high concentrations of cisplatin revealed transcriptomic changes in potential key drivers of drug resistance, such as KLF4. Among the strongest changes was also induction of IL6 in resistant cells and the expression was further increased in response to cisplatin. Also, several other components of IL6 signaling were affected, further supporting previous observations on its importance in malignant transformation and development of drug resistance in ovarian cancer.High-grade serous ovarian cancer (HGSOC) is the most common ovarian cancer subtype and accounts for 80% of the deaths caused by the disease. The prognosis of HGSOC is poor as most diagnosis is at late stages of the disease when the 10-year survival rate is only in the order of 15%. The main strategy for treatment involves surgical removal of the tumor tissue and chemotherapy 1 . Platinium compounds, such as cisplatin, in combination with taxane are typically used in chemotherapy. However, recurrence of the cancer is frequent and most of the patients will eventually become refractory to the treatment 2 . In order to improve the prognosis of the patients with HGSOC, new biomarkers enabling early diagnosis of the disease as well as new therapeutic strategies overcoming the drug resistance are needed 1,3 . Detailed characterization of the molecular mechanisms leading to drug resistance is important for development of improved therapies.The molecular mechanisms leading to drug resistance can be heterogeneous and complex 4 . In addition to genetic factors, the development may involve epigenetic changes, which enable tumor cells, and possibly non-transformed cells in the microenvironment, to adapt and lose sensitivity to drug treatment. DNA methylation and transcriptional changes associated with drug resistance have been detected in several genomic sites in both cell lines and patient samples [5][6][7][8] . For example, methylation and transcriptional silencing of the MLH1 gene have been repeatedly associated with cisplatin resistance 8,9 . Although several candidate driver genes for cisplatin resistance have been ...

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Identification of Prognostic Groups in High-Grade Serous Ovarian Cancer Treated with Platinum–Taxane Chemotherapy

Cited by 35 publications

References 47 publications

Implementing rapid, robust, cost-effective, patient-centred, routine genetic testing in ovarian cancer patients

Implementing rapid, robust, cost-effective, patient-centred, routine genetic testing in ovarian cancer patients

Treatment related toxicity in BRCA1-associated epithelial ovarian cancer – is DNA repairing impairment associated with more adverse events?

DNA methylation and Transcriptome Changes Associated with Cisplatin Resistance in Ovarian Cancer

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