Presented at SGO - March 19, 2016

Transcription

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2 Homologous Recombination Deficiency (HRD) Score Shows Superior Association with Outcome Compared to its Individual Score Components (LOH, TAI, and LST Scores) in Platinum Treated Serous Ovarian Cancer Gordon Mills 1, Kirsten M. Timms 2, Julia Reid 2, Alexander Gutin 2, Thomas Krivak 3, Bryan Hennessy 1, James Paul 4, Robert Brown 4, Jerry S. Lanchbury 2, Euan A. Stronach 4 1. University of Texas MD Anderson Cancer Center, Houston, TX 2. Myriad Genetics, Inc., Salt Lake City, UT 3. Western Pennsylvania Hospital, Pittsburgh, PA 4. Imperial College London, London, United Kingdom

3 DISCLOSURE Consultant and/or Research Funding: Adelson Medical Research Foundation, Allostery, AstraZeneca, Critical Outcome Technologies, GSK, Immunomet, Illumina, Karus, Nanostring, Nuevolution, Pfizer, Provista Diagnostics, Signalchem Lifesciences, Symphogen, Tau Therapeutics, Takeda, Millenium, Tarveda Shareholder: Catena Pharmaceuticals, Immunomet PTV Ventures, Spindle Top Ventures Licensed Technology: LOH score licensed to Myriad Genetics Kirsten M. Timms, Julia Reid, Alexander Gutin, Jerry S. Lanchbury are employees of Myriad Genetics, Inc.

4 Background Homologous recombination deficiency (HRD) is a measure of genomic instability that signals response to platinum and PARP inhibitors. There may be many causes of HRD in addition to mutations in cancer predisposition genes. Previous studies have suggested that a 3-biomarker HRD score is a superior predictive marker to any of the individual components. We present the first direct evaluation of the utility of the 3-biomarker score and the individual score components in platinum-treated serous ovarian cancer (SOC).

5 Background: 3-Biomarker HRD Score An HR deficiency (HRD) score, which is a measure of genome instability, has been developed as the sum of three independent biomarkers: TAI (telomeric-allelic imbalance) 1 LST (large-scale state transitions) 2 LOH (loss of heterozygosity) 3 HRD score is calculated from SNPderived whole genome profiling TAI LST LOH 1. Birbak NJ, et al. Cancer Discovery. 2012; 2: Popova T, et al. Cancer Research. 2012; 72: Abkevich V, et al. Br J Cancer. 2012; 107(10):1776.

6 Background: HRD Score High/Low Cut-Off An HRD cut-off (42) was previously developed in a training cohort (n=1,058) of chemotherapy naïve ovarian and breast tumors using 95% sensitivity to detect BRCA1/2 deficient tumors. 4-7 Tumors with a high HRD score ( 42) were defined as HR deficient. 4. Timms, et al. Br Cancer Res. 2014; 16: Hennessy BT, et al. J Clin Oncol. 2010; 28: TCGA Network. Nature. 2012; 490: TCGA Research Network. Nature. 2011; 474:6609.

7 4. Timms, et al. Br Cancer Res. 2014; 16: Hennessy BT, et al. J Clin Oncol. 2010; 28: TCGA Network. Nature. 2012; 490: TCGA Research Network. Nature. 2011; 474:6609. Overarching Goal The overarching goal is to develop a robust, practical and effective approach to identify patients likely to benefit from established platinum based and emerging PARP inhibitor based therapies. Study Aim The aim of this analysis was to evaluate the performance of the 3 individual component scores relative to the combined 3- biomarker score in predicting response to platinum based therapy.

8 4. Timms, et al. Br Cancer Res. 2014; 16: Hennessy BT, et al. J Clin Oncol. 2010; 28: TCGA Network. Nature. 2012; 490: TCGA Research Network. Nature. 2011; 474:6609. Methods In the same training cohort (n=1,058), a cut-off for HRD (42) and each of the 3 HRD components was determined based on a 95% sensitivity to detect BRCA1/2 deficient tumors. 4-7 LOH 8; TAI 10; LST 18 Cox proportional hazards models stratified by cohort were applied in a retrospective analysis of an independent study cohort (n=859) samples from four studies examining the use of platinum based therapy. The dichotomized scores (high, low) were tested individually and then compared to the combined HRD score in bivariate models.

9 Results: Distributions in Study Ovarian Cohort n=859 No bimodal distribution of scores above and below individual biomarker cut-offs Number of patients Number of patients 5. Hennessy BT, et al. J Clin Oncol. 2010; 28: TCGA Research Network. Nature. 2011; 474: Bannerjee et al. Ann Oncol. 2013;24(3):679.

10 Results: Distributions in Study Ovarian Cohort n=859 BRCA1/2 mutations in white Number of patients Number of patients 5. Hennessy BT, et al. J Clin Oncol. 2010; 28: TCGA Research Network. Nature. 2011; 474: Bannerjee et al. Ann Oncol. 2013;24(3):679.

11 Results: Univariate Analysis of The 3-biomarker HRD score reached significance for both PFS and OS. Dichotomous Scores PFS OS High/Low P Value HR P Value HR HRD 2x x

12 Results: Univariate Analysis of All of the individual component scores reached significance for both PFS and OS. Dichotomous Scores PFS OS High/Low P Value HR P Value HR HRD 2x x LOH 5x x

13 Results: Univariate Analysis of All of the individual component scores reached significance for both PFS and OS. Dichotomous Scores PFS OS High/Low P Value HR P Value HR HRD 2x x LOH 5x x TAI 9x x

14 Results: Univariate Analysis of All of the individual component scores reached significance for both PFS and OS. Dichotomous Scores PFS OS High/Low P Value HR P Value HR HRD 2x x The HRD score was more significant than any of the component scores. LOH 5x x TAI 9x x LST 1x x

15 Results: Bivariate Analysis of None of the individual component scores reached significance for either PFS or OS. Dichotomous Scores PFS OS High/Low P Value HR P Value HR HRD x LOH

16 Results: Bivariate Analysis of None of the individual component scores reached significance for either PFS or OS. Dichotomous Scores PFS OS High/Low P Value HR P Value HR HRD x LOH HRD TAI

17 Results: Bivariate Analysis of None of the individual component scores reached significance for either PFS or OS. The HRD score is a better predictor of outcomes for platinum treated patients than the individual biomarker component scores. Dichotomous Scores PFS OS High/Low P Value HR P Value HR HRD x LOH HRD TAI HRD LST

18 False Positive and Negative Results from Individual Scores LOH Score Potential False Positives LOH Diagnostic Accuracy: 85% Potential False Negatives HRD Comparison TAI LST LOH False Positives False Negatives True Positives True Negatives Diagnostic Accuracy % HRD Score

19 Conclusions A combined 3-biomarker HRD score is a superior predictor of survival of platinum treated ovarian cancer patients than any of the individual biomarker components (LOH, TAI, LST). HRD score in combination with BRCA1/2 mutation status is currently being evaluated as a predictor of response to platinum and PARP inhibitors in multiple prospective clinical studies.