NEW YORK (GenomeWeb News) – Researchers from the Dana-Farber Cancer Institute have come up with a risk score based on the expression of almost two-dozen DNA repair-related genes that they say can help predict ovarian cancer outcomes following platinum-based chemotherapy.
As reported online recently in the Journal of the National Cancer Institute, the team tracked down these genes through a DNA repair-centered analysis of expression data generated for the Cancer Genome Atlas project. The search stemmed from the hypothesis that ovarian cancer cells' ability to repair chemotherapy-induced DNA damage might influence treatment response and, ultimately, outcomes.
When they assessed TCGA expression data for 151 DNA damage repair genes in ovarian tumors from hundreds of women with advanced ovarian cancer, as well as corresponding clinical data, the researchers found a subset of 23 genes from four DNA repair pathways with expression that roughly corresponded to overall survival. From there, they developed a risk score for evaluating ovarian cancer tumors based on higher- or lower-than-usual expression at these genes.
In the TCGA dataset, and in the two independent, previously published datasets used for validation, the team found that individuals with tumors that scored low on the 23-gene predictor had significantly worse overall survival rates following platinum-based chemotherapy treatment than those with tumors scoring higher. Higher scores also coincided with improved treatment response, progression-free survival, and recurrence-free survival.
"The recent release of TCGA gene expression data in epithelial ovarian cancer is unprecedented in size and comprehensiveness," Dana-Farber physician and radiation oncology researcher David Kozono, the study's senior author, and colleagues wrote.
"By mining this resource, and applying biologic rationale," they added, "we have created a durable score that provides predictive information regarding a tumor's intrinsic sensitivity or resistance to first-line platinum and taxane chemotherapy."
In an editorial set to appear in the same issue of JNCI, three University of Washington obstetrics and gynecology researchers said the study points to some interesting new questions for understanding ovarian cancer itself.
But the editorial authors cautioned that the newly devised DNA repair score is not yet suitable for use in the clinic, since it did not fit all of the features of the underlying hypothesis used to establish it and, for one of the two validation datasets, only showed statistical significance when some samples were excluded.
That trio also expressed concern over potential discrepancies in findings from TCGA data depending on the analytical method used, noting that "TCGA samples were collected for molecular annotation, not chosen to be representative or to answer specific outcomes questions, likely explaining why the TCGA set behaves differently than most other collections."
"The development of predictive biomarkers is critical to the successful application of individualized therapy," Elizabeth Swisher, corresponding author on the editorial, and her colleagues wrote.
"The study … is an important effort in that direction but demonstrates the challenges we face as we attempt to utilize large datasets to develop personalized genomic medicines," they added. "The premature application of inadequately validated biomarkers may adversely impact the successful implementation of individualized therapies."
The study's authors emphasized that prospective clinical trials will be needed to test predictive value of their DNA damage repair gene-based risk score in the future. Still, they are optimistic about the prospect of applying it to not only guide existing ovarian cancer treatments, but also others developed down the road.
"With additional prospective validation in clinical trials, we hope that the score can become a powerful tool that is useful in stratifying advanced-stage ovarian cancer patients toward optimal treatments incorporating new treatment regimens [versus] current standard of care," they wrote.