The Lynx Group

Genomic Instability Score Predicts Survival in Patients with Ovarian Cancer

May 2016, Vol 7, No 4

A higher score on a composite index of homologous recombination deficiency (HRD), indicating genomic instability, correlated with improved progression-free survival (PFS) and overall survival (OS) in patients with ovarian cancer who have received platinum-containing chemotherapy, according to results presented at the 2016 Society of Gynecologic Oncology annual meeting.

An HRD score that met or exceeded the predefined threshold reduced the hazard ratio for PFS and OS by approximately 33%. A comparison of the HRD score with its individual biomarker components showed that the composite score was significantly better than its individual markers for predicting outcome.

“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 B. Mills, MD, PhD, Co-director, Zayed Institute for Personalized Cancer Therapy, M.D. Anderson Cancer Center, Houston, TX.

“The HRD score, in combination with <em>BRCA1/2</em> mutation status, is currently being evaluated as a predictor of response to platinum chemotherapy and PARP [poly ADP ribose polymerase] inhibitors in multiple prospective clinical studies,” he added.

The HRD score comprises the scores of telomeric-allelic imbalance (TAI), large-scale state transitions (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 cohort of 1058 patients with untreated ovarian and breast cancers. The results showed that an HRD score cutoff of 42 yielded the best predictive results.

For validating the HRD score, Dr Mills and colleagues retrospectively investigated the score in 858 ovarian tumor samples from patients in clinical trials of platinum-based chemotherapy. The scores for LOH, TAI, and LST were tested individually and were then compared with the composite score.

By univariate analysis, the combined HRD score achieved statistical significance for PFS. Each of the individual markers also demonstrated significant predictive capability. However, application of the HRD score to the tumor specimens resulted in a greater significance than any of the individual components, said Dr Mills.

In a 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 hazard ratios of approximately 0.70 for PFS in all 3 bivariate comparisons.

An 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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