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“The findings could aid in the development of an algorithm for triaging patients to neoadjuvant approaches versus primary debulking…”
TAMPA (FRONTLINE MEDICAL NEWS) – High levels of FABP4 and ADH1B gene expression in patients with high-grade serous ovarian cancer are associated with significantly increased risk of residual disease after primary debulking surgery, according to an analysis of two large-scale, publicly available genomic data sets.
The findings could aid in the development of an algorithm for triaging patients to neoadjuvant approaches versus primary debulking, said Dr. Anil K. Sood at the annual meeting of the Society of Gynecologic Oncology.
In 491 patients from The Cancer Genome Atlas (TCGA) data set, and 189 from the Tothill data set, survival was significantly greater in patients with no residual disease than in those with any degree of residual disease. In both data sets, 47 prosets representing 38 different genes – significant in both data sets at a 10% false-discovery rate – were identified.
After several sets of validation, including qualitative validation in two additional data sets, and quantitative validation using primary ovarian cancer samples from 139 individuals, FABP4 and ADH1B were found to have the highest levels of expression, with substantial enrichment of FABP4 in those with residual disease in both the TCGA and Tothill data sets, Dr. Sood of the University of Texas M.D. Anderson Cancer Center, Houston, reported.
When FABP4 and ADH1B were plotted together, it was apparent that they were coordinated. That is, “when one is up, the other tends to be up,” he said.
Furthermore, the changes weren’t subtle but were bimodal, he noted.
“If we consider those individuals who have the highest quartile of these genes – the top 25% – 88% of the individuals had residual disease when either FABP4 or ADH1B was elevated,” he said, adding that looking at the second gene didn’t change things much because the two genes tend to be elevated jointly.
“To look at this in another way, the odds ratio was 5.5 for residual disease with high FABP4 levels, … so if you look at those individuals with residual disease, 30 of 35 had high FABP4 levels, compared with those with low FABP4, where 54 out of 104 had residual disease,” he said.
The findings are not surprising as FABP4 was shown in a prior study to play a prominent role in promoting omental metastasis and is considered a potential target for therapeutic approaches. However, the findings are important, because gross residual disease following primary cytoreduction is the best predictor of overall survival in patients with high-grade serous ovarian carcinoma, and the accurate identification of patients who will have residual disease has remained elusive.
“Outcome predictors could be very useful in predicting who would most likely benefit from surgical care up front versus potentially doing surgery in an interval setting following neoadjuvant chemotherapy,” he said, noting that most prior attempts at identifying outcome predictors have focused on identifying patients most likely to undergo optimal debulking.
Furthermore, imaging parameters and circulating markers have not been particularly reliable predictors of residual disease following surgery.
“We have learned over the last several years that the greatest differences in outcomes really tend to be for those patients who have no gross residual, compared with those left with any degree of residual,” he said, noting that this information prompted the current search for molecular predictors of residual disease, which is based on the premise that underlying biology could be different in tumors that are not fully resectable.
Though limited by the possibility that gene expression levels are different in primary versus metastatic disease sites, and by varying degrees of aggressiveness in debulking approaches at different cancer centers included in the data set, the findings nonetheless suggest that patients with high tumor expression of FABP4 may be candidates for neoadjuvant chemotherapy, Dr. Sood concluded.