open access: Editorial: Molecular Scores to Predict Ovarian Cancer Outcomes: A Worthy Goal, but Not Ready for Prime Time

Molecular Scores to Predict Ovarian Cancer Outcomes: A Worthy Goal, but Not Ready for Prime Time

"... The premature application of inadequately validated biomarkers may adversely impact the successful implementation of individualized therapies."

open access: A DNA Repair Pathway–Focused Score for Prediction of Outcomes in Ovarian Cancer Treated With Platinum-Based Chemotherapy (serous)

A DNA Repair Pathway–Focused Score for Prediction of Outcomes in Ovarian Cancer Treated With Platinum-Based Chemotherapy

Patient Samples

We extracted clinical data for 511 patients with serous ovarian cystadenocarcinoma from The Cancer Genome Atlas (TCGA) database (44) website (http://tcga-data.nci.nih.gov) on February 17, 2011, representing the largest available dataset of epithelial ovarian cancer gene expression profiles (see Supplementary Table 2, available online, for further details on which ovarian cancer samples were included in this study). These were all the patients for whom full sets of tumor gene expression data were available for download..... 


Table 1

Clinicopathologic characteristics of ovarian cancer patients in The Cancer Genome Atlas (TCGA) dataset^*

Table 2

Genes in platinum-specific DNA repair pathways that were used to construct the score^*

(For each gene, “high” means higher than median gene expression was associated with improved overall survival in The Cancer Genome Atlas dataset, and “low” means higher than median gene expression was associated with worse overall survival  

                                  ^{~~~~~~~~~~~~~~}

CONTEXT AND CAVEATS

Prior knowledge

At present, there are no effective prognostic tools for prediction of response in ovarian cancer patients, a majority of whom are diagnosed with an advanced stage (stages III and IV) and undergo surgical debulking followed by and platinum-based chemotherapy.

Study design

Gene expression data was extracted from The Cancer Genome Atlas (TCGA) database for patients with advanced ovarian cancer, and a molecular score was developed by focusing exclusively on the genes involved in platinum-induced DNA damage repair pathways. Patients were divided into low (0–10) and high (11–20) scores, and the prognostic value of the score for overall survival, recurrence-free survival, and progression-free survival was assessed. Data were validated in two independent datasets.

Contribution

Patients with high scores showed statistically significant associations with improved overall survival compared with patients with low scores. The score was predictive of overall survival, recurrence-free survival, and progression-free survival in ovarian cancer patients who received first-line platinum-based chemotherapy.

Implication

This score has the potential to become an important prognostic tool to determine whether advanced-stage ovarian cancer patients will benefit from first-line platinum-based chemotherapy.

Limitation

The score has not been tested prospectively in a clinical trial.

abstract: Rare Mutations in XRCC2 Increase the Risk of Breast Cancer.

 Blogger's Note: see recent post for a null finding XRCC/Lynch Syndrome

Rare Mutations in XRCC2 Increase the Risk of Breast Cancer.:

Rare Mutations in XRCC2 Increase the Risk of Breast Cancer.

Am J Hum Genet. 2012 Mar 28;


Abstract

An exome-sequencing study of families with multiple breast-cancer-affected individuals identified two families with XRCC2 mutations, one with a protein-truncating mutation and one with a probably deleterious missense mutation. We performed a population-based case-control mutation-screening study that identified six probably pathogenic coding variants in 1,308 cases with early-onset breast cancer and no variants in 1,120 controls (the severity grading was p<0.02). We also performed additional mutation screening in 689 multiple-case families. We identified ten breast-cancer-affected families with protein-truncating or probably deleterious rare missense variants in XRCC2. Our identification of XRCC2 as a breast cancer susceptibility gene thus increases the proportion of breast cancers that are associated with homologous recombination-DNA-repair dysfunction and Fanconi anemia and could therefore benefit from specific targeted treatments such as PARP (poly ADP ribose polymerase) inhibitors. This study demonstrates the power of massively parallel sequencing for discovering susceptibility genes for common, complex diseases.

abstract: DNA repair gene polymorphisms and risk of early onset colorectal cancer in Lynch syndrome (eg. BRCA2, MSH3 (polymorphisms)...)

DNA repair gene polymorphisms and risk of early onset colorectal cancer in Lynch syndrome:

Source:Cancer Epidemiology, Volume 36, Issue 2


DNA repair plays a pivotal role in maintaining genomic integrity with over 130 genes involved in various repair pathways that include base excision repair, nucleotide excision repair, double strand break repair and DNA mismatch repair. Polymorphisms within genes that are involved in these processes have been widely reported to be associated with cancer susceptibility in an extensive range of malignancies that include colorectal cancer (CRC).

Lynch syndrome is caused by inherited germline mutations in DNA mismatch repair genes, predominantly in MLH1 and MSH2, that predispose to a variety of epithelial malignancies, most notably CRC. Despite being a relatively well understood hereditary cancer syndrome there remain several questions in relation to genetic influences on disease expression. Since Lynch syndrome is associated with a breakdown in DNA mismatch repair variation in other DNA repair genes may influence disease expression.

In this report we have genotyped 424 Australian and Polish Lynch syndrome participants for eight common DNA repair gene polymorphisms to assess any association with the age of CRC onset.

 The DNA repair gene SNPs included in the study were: BRCA2 (rs11571653), MSH3 (rs26279), Lig4 (rs1805386), OGG1 (rs1052133), XRCC1 (rs25487), XRCC2 (rs3218536 and rs1799793) and XRCC3 (rs861539). Cox multi-variant regression modelling failed to provide any convincing evidence of an effect in any of the polymorphisms analysed. The data suggest that polymorphisms in DNA repair genes do not contribute to cancer risk in a population of CRC patients who are at increased risk of disease as a result in a deficiency of DNA mismatch repair.

abstract: Pre-Treatment Tumor Expression of ERCC1 in Women with Advanced Stage Epithelial Ovarian Cancer is Not Predictive of Clinical Outcomes: A GOG study

Conclusions

ERCC1 expression, measured by IHC in pre-treatment tumor specimens, using a highly specific antibody, has limited clinical value in patients with advanced EOC treated with platinum and taxane based chemotherapy.

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Highlights

► ERCC1 tumor expression in advanced EOC is not associated with patient survival.
► Common polymorphisms in ERCC1 were not associated with ERCC1 immunohistochemical expression.

abstract: Cochrane Collaboration review: DNA-repair pathway inhibitors for the treatment of ovarian cancer (PARP inhibitors)

"Our objective was to compare effectiveness and side effects of PARP inhibitors compared to conventional chemotherapy in women with ovarian cancer. The identification of a safe dose of AZD2281 (a PARP inhibitor) has been found by small non randomised trials, with encouraging results. For ovarian cancer, there are currently two ongoing RCTs, but outcome data are not yet available. Results of these trials are awaited to determine if DNA repair inhibitors have a role in addition to conventional chemotherapy in the treatment of ovarian cancer."

Main results
The search strategy identified 473 unique references of which 461 were excluded on the basis of title and abstract. The remaining 12 articles were retrieved in full, but none satisfied the inclusion criteria. However, two ongoing randomised phase II clinical trials were identified from the clinical trials databases that met our inclusion criteria, but no preliminary data were available.


Authors' conclusions

There are to date no published RCT data on the effectiveness and side effects of DNA-repair pathways inhibitors used alone or in association with conventional chemotherapy in the treatment of ovarian cancer. On-going trials have been identified and results are awaited and will be included in future updates of this review.

media article: The inherited malignancy of breast cancer (and ovarian cancer)

Note: good article, albeit complicated subject matter - excerpts of important information: