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Poster display

2504 - 3-biomarker HRD score versus individual biomarker (LOH, TAI, LST) scores in platinum treated serous ovarian cancer (SOC)

Date

10 Oct 2016

Session

Poster display

Presenters

Jerry Lanchbury

Citation

Annals of Oncology (2016) 27 (6): 15-42. 10.1093/annonc/mdw363

Authors

J. Lanchbury1, K. Timms1, J. Reid1, E. Stronach2, A. Gutin1, T. Krivak3, B. Hennessy4, J. Paul2, R. Brown2, R. Nix1, Z. Sangale1, E. Hughes1, V. Abkevich1, G.B. Mills5

Author affiliations

  • 1 Clinical Research, Myriad Genetics Inc, 84108 - Salt Lake City/US
  • 2 Surgical Oncology, Imperial College London-South Kensington Campus, SW7 2AZ - London/GB
  • 3 Gynecologic Oncology, Western Pennsylvania Hospital, 15224 - Pittsburgh/US
  • 4 Medical Oncology, MD Anderson Cancer Center, 77094 - Houston/US
  • 5 Systems Biology, MD Anderson Cancer Center, 77030 - Houston/US
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Resources

Abstract 2504

Background

Previous studies have shown that tumors with defects in the homologous recombination (HR) pathway show improved response to DNA-damaging agents. To identify tumors likely to benefit from these therapies, we developed a 3-biomarker HR deficiency (HRD) score that is the sum of three independent measures of HRD (loss of heterozygosity (LOH), telomeric-allelic imbalance (TAI), large-scale state transitions (LST)). Previous studies have shown that the HRD score is a better prognostic marker of PFS and OS relative to the individual scores in platinum treated SOC. Here we evaluate the correlation between, and specificity of, the 3-biomarker HRD and individual scores to quantify potential false positive and negative results.

Methods

An HRD threshold (≥42) was developed in a training cohort of ovarian and breast tumors using a cut-off of 95% sensitivity to detect BRCA1/2 deficient tumors. A threshold for each HRD component was determined using the same cohort and method (LOH ≥8, TAI ≥10, LST ≥18). The correlation between the dichotomized scores (high, low), and specificity for classifying tumors as BRCA1/2 deficient, for the HRD score and component scores was retrospectively evaluated in 859 SOC tumors.

Results

The correlation between the HRD score and the LOH score was 0.872. There were 126 discordant scores, including 102 cases with high LOH scores and low HRD scores. These represent potential false positives based on LOH alone. Similarly, 24 samples with low LOH scores had high HRD scores (potential false negatives). Similar behavior was observed for TAI (correlation coefficient 0.905, 95 discordant scores) and LST (correlation coefficient 0.941, 88 discordant scores). Specificity was highest for the HRD score in both the training and test cohorts (0.897 and 0.796) compared to any of the component scores (LOH: 0.624 and 0.668; TAI: 0.766 and 0.690; LST: 0.759 and 0.672).

Conclusions

Here we show that the use of a single HRD biomarker may misinform treatment decisions in SOC relative to the combined 3-biomarker score. The combined HRD assay, which has been validated on FFPE SOC tumor tissue, warrants evaluation in a prospective study sample set in a rigorously validated laboratory.

Clinical trial identification

none

Legal entity responsible for the study

N/A

Funding

Myriad Genetics, Inc

Disclosure

J. Lanchbury: Myriad Employee compensated with salary and stock options. K. Timms: Myriad Genetics Employee – Receive salary and stock options. J. Reid, A. Gutin, V. Abkevich R. Nix, Z. Sangale: Myriad Employee – Salary and stock options. All other authors have declared no conflicts of interest.

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