L Wang15, S M Dehm2, D W Hillman3, H Sicotte3, W Tan4, M Gormley5, V Bhargava5, R Jimenez6, F Xie7, P Yin7, S Qin7, F Quevedo8, B A Costello8, H C Pitot8, T Ho9, A H Bryce9, Z Ye10, Y Li3, P Eiken11, P T Vedell3, P Barman3, B P McMenomy11, T D Atwell11, R E Carlson3, M Ellingson12, B W Eckloff13, R Qin3, F Ou3, S N Hart3, H Huang10, J Jen14, E D Wieben13, K R Kalari3, R M Weinshilboum7, L Wang15, M Kohli16. 1. Division of Biomedical Statistics and Informatics, Department of Health Sciences, Rochester, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, USA. 2. Masonic Cancer Center, University of Minnesota, Minneapolis, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, USA; Department of Urology, University of Minnesota, Minneapolis, USA. 3. Division of Biomedical Statistics and Informatics, Department of Health Sciences, Rochester, USA. 4. Department of Medicine, Mayo Clinic, Jacksonville, USA. 5. Janssen Research and Development, Spring House, Philadelphia, USA. 6. Department of Pathology and Lab Medicine, Mayo Clinic, Rochester, USA. 7. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, USA. 8. Department of Oncology, Mayo Clinic, Rochester, USA. 9. Department of Medicine, Mayo Clinic, Scottsdale, USA. 10. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, USA. 11. Department of Radiology, Mayo Clinic, Rochester, USA. 12. Medical Genetics, Mayo Clinic, Rochester, USA. 13. Medical Genome Facility, Mayo Clinic, Rochester, USA. 14. Medical Genome Facility, Mayo Clinic, Rochester, USA; Division of Experimental Pathology and Laboratory Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Mayo Clinic, Rochester, USA. 15. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, USA. Electronic address: wang.liewei@mayo.edu. 16. Department of Oncology, Mayo Clinic, Rochester, USA. Electronic address: kohli.manish@mayo.edu.
Abstract
Background: Genomic aberrations have been identified in metastatic castration-resistant prostate cancer (mCRPC), but molecular predictors of resistance to abiraterone acetate/prednisone (AA/P) treatment are not known. Patients and methods: In a prospective clinical trial, mCRPC patients underwent whole-exome sequencing (n = 82) and RNA sequencing (n = 75) of metastatic biopsies before initiating AA/P with the objective of identifying genomic alterations associated with resistance to AA/P. Primary resistance was determined at 12 weeks of treatment using criteria for progression that included serum prostate-specific antigen measurement, bone and computerized tomography imaging and symptom assessments. Acquired resistance was determined using the end point of time to treatment change (TTTC), defined as time from enrollment until change in treatment from progressive disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using logistic regression, Fisher's exact test, single and multivariate analyses. Cox regression models were utilized for determining association of genomic and transcriptomic alterations with TTTC. Results: At 12 weeks, 32 patients in the cohort had progressed (nonresponders). Median study follow-up was 32.1 months by which time 58 patients had switched treatments due to progression. Median TTTC was 10.1 months (interquartile range: 4.4-24.1). Genes in the Wnt/β-catenin pathway were more frequently mutated and negative regulators of Wnt/β-catenin signaling were more frequently deleted or displayed reduced mRNA expression in nonresponders. Additionally, mRNA expression of cell cycle regulatory genes was increased in nonresponders. In multivariate models, increased cell cycle proliferation scores (≥ 50) were associated with shorter TTTC (hazard ratio = 2.11, 95% confidence interval: 1.17-3.80; P = 0.01). Conclusions: Wnt/β-catenin pathway activation and increased cell cycle progression scores can serve as molecular markers for predicting resistance to AA/P therapy.
Background: Genomic aberrations have been identified in metastatic castration-resistant prostate cancer (mCRPC), but molecular predictors of resistance to abiraterone acetate/prednisone (AA/P) treatment are not known. Patients and methods: In a prospective clinical trial, mCRPC patients underwent whole-exome sequencing (n = 82) and RNA sequencing (n = 75) of metastatic biopsies before initiating AA/P with the objective of identifying genomic alterations associated with resistance to AA/P. Primary resistance was determined at 12 weeks of treatment using criteria for progression that included serum prostate-specific antigen measurement, bone and computerized tomography imaging and symptom assessments. Acquired resistance was determined using the end point of time to treatment change (TTTC), defined as time from enrollment until change in treatment from progressive disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using logistic regression, Fisher's exact test, single and multivariate analyses. Cox regression models were utilized for determining association of genomic and transcriptomic alterations with TTTC. Results: At 12 weeks, 32 patients in the cohort had progressed (nonresponders). Median study follow-up was 32.1 months by which time 58 patients had switched treatments due to progression. Median TTTC was 10.1 months (interquartile range: 4.4-24.1). Genes in the Wnt/β-catenin pathway were more frequently mutated and negative regulators of Wnt/β-catenin signaling were more frequently deleted or displayed reduced mRNA expression in nonresponders. Additionally, mRNA expression of cell cycle regulatory genes was increased in nonresponders. In multivariate models, increased cell cycle proliferation scores (≥ 50) were associated with shorter TTTC (hazard ratio = 2.11, 95% confidence interval: 1.17-3.80; P = 0.01). Conclusions: Wnt/β-catenin pathway activation and increased cell cycle progression scores can serve as molecular markers for predicting resistance to AA/P therapy.
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