May 2016, Vol. 5, No. 4

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Genomic Instability Score Predicts Survival in Ovarian Cancer

Gordon Mills, MD, PhD

Society of Gynecologic Oncology

Genomic Instability Score Predicts Survival in Ovarian CancerA higher score on a composite index of homologous recombination deficiency (HRD) correlated with improved progression-free survival (PFS) and overall survival (OS) in ovarian cancer treated with platinum-containing chemotherapy, results of a tissue-based validation study showed.

An HRD score that met or exceeded the predefined threshold reduced the hazard ratio (HR) for PFS and OS by about one-third. Comparison of the HRD score with its individual biomarker components showed that the composite performed significantly better for predicting outcome, as reported at the Society of Gynecologic Oncology meeting in San Diego.

“We demonstrated that an algorithmic measurement of 3 biomarkers of genomic instability is a superior predictor of outcome in platinum-treated serous ovarian cancer than any of the individual score components,” said Gordon Mills, MD, PhD, Chair, Department of Systems Biology, The University of Texas MD Anderson Cancer Center in Houston. “The HRD score, in combination with BRCA1/2 mutation status, is currently being evaluated as a predictor of response to platinum chemotherapy and PARP inhibitors in multiple prospective clinical studies.”

The HRD score comprises telomeric-allelic imbalance (TAI), large-scale state transition (LST), and loss of heterozygosity (LOH), each of which has been validated as a marker of genomic instability associated with DNA-damaging treatment. The score was evaluated in a training cohort of 1058 patients with untreated ovarian and breast cancers. The results showed that an HRD cutoff of 42 yielded the best predictive results.

For validation of the HRD score, Dr Mills and colleagues retrospectively investigated the score in 858 ovarian tumor samples from patients involved in clinical trials of platinum-based chemotherapy. Scores for LOH, TAI, and LST were tested individually and then compared to the HRD score in bivariate models.

By univariate analysis, the HRD score achieved statistical significance for PFS (HR, 0.66, P = 2 × 10-6) and OS (HR, 0.55; P = 1 × 10-8). Each of the individual markers also demonstrated significant predictive capability. However, application of the HRD score to the tumor specimens resulted in a higher level of significance than any of the individual components, said Dr Mills.

In the bivariate analysis, the composite score remained a significant predictor of PFS and OS, but none of the 3 biomarkers retained statistical significance. The HRD score was associated with HRs of about 0.70 for PFS in all 3 bivariate comparisons (P = .045 to P = .007). The bivariate analysis of OS yielded HRs of about 0.60 for the HRD score for all 3 comparisons (P = .008 to P = 2 × 10-4).

Analysis of potential false-positive and false-negative results showed that the individual biomarkers had an overall diagnostic accuracy of 85% to 90% versus the composite HRD score.

“The HRD score added significantly to each of the individual (component) scores for both progression-free survival and overall survival,” said Dr Mills.

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