Abstract 426: Variant allele frequency changes and treatment responses in advanced prostate cancer
Authors: Vlachostergios Panagiotis J. , Molina Ana M. , Nanus David M. , Beltran Himisha , Tagawa Scott T. 
Published: August 2018

Abstract
Introduction: Serial monitoring of genomic alterations in tumors is gaining interest as a research tool to better understand the biology of disease progression in different tumor types, including prostate cancer (PC). We hypothesized that intra-patient enrichment of mutations shared among different tumor samples from patients with advanced PC (castration-resistant or neuroendocrine) may parallel their clinical behavior in response to systemic therapy.
Methods: We examined patients with PC enrolled in our prospective Precision Medicine cohort, with at least 2 consecutive tissue or/and liquid biopsies available. By whole exome sequencing (WES) we assessed the variant allele frequencies (VAF) in gene alterations which were shared between spatiotemporally different samples from the same patients. We investigated associations between VAF changes and radiologic responses using the Chi-square test.
Results: Six patients with paired WES from samples 1-15 months apart with advanced PC were studied. Distribution of VAF in shared gene alterations and treatment outcomes (response vs. progression of disease) are presented in Table 1. In progressing patients (N=5), 20/25 (80%) of VAFs of shared genes were increased while 5/25 (20%) were reduced. In the one responding patient, 6/6 (100%) VAF of shared genes were decreased between samples. A significant association was found between VAF and radiologic responses (p = 0.0006).
Conclusions: Serial monitoring of VAF of shared genes between spatiotemporally distinct tumors within the same patient may assist in predicting radiologic responses to systemic therapies in advanced PC. Testing of these hypothesis-generating analysis results in larger, prospective studies is suggested.
Table 1.
Patient 1Patient 2Patient 3Patient 4Patient 5Patient 6Sample Asiteboneboneprostatelymph nodelymph nodeprostateGene – VAF (%)APC: 45GRIN3B: 20TP53: 26.8TP53: 75.8TP53: 71.4TP53: 86.7CAPN9: 51.6BRCA2: 38.1BRCA2: 31.2CSMD1: 67.1APC: 73.7TRIM27: 39.2RCOR3: 57.1ZFHX3: 29.8ANK2: 39.1ARHGAP4: 88.6AICF: 65.4ARHGAP36: 49.2DNA2: 14.4CPS1: 100DUSP12: 51.3SCN3A: 62.8LAMA4: 36PDL1M1: 19.4ZNF335: 65.8SLCO3A1: 76.7RPTN: 27.5LRIG3: 19.8SEC14L1: 75SIRT2: 53,4ROR2: 31.1Sample Bsitebonebonelymph nodeliverbloodliverGene – VAF (%)APC: 75GRIN3B: 58.7TP53: 44.7TP53: 88.7TP53: 6.4%TP53: 60.6CAPN9: 89.4ZFHX3: 85BRCA2: 40CSMD1: 73.3APC: 0.8%TRIM27: 36.1RCOR3: 64DNA2: 50ANK2: 85.7ARHGAP4: 92.7AICF: 51.9ARHGAP36: 88.2PDL1M1: 53.7CPS1: 98.4DUSP12: 58.8SCN3A: 41LAMA4: 66.7LRIG3: 35.5ZNF335: 53.1SLCO3A1: 27.9RPTN: 58.2SEC14L1: 67.1SIRT2: 35.7ROR2: 52.5Sample CsitebloodGene – VAF (%)BRCA2: 71.6TreatmentLeuprolideEnzalutamideCisplatin/ Docetaxel, EtoposideEnzalutamideDocetaxelCarboplatin/ EtoposideRadiologic assessmentprogressionprogressionprogressionprogressionprogressionresponse
Citation Format: Panagiotis J. Vlachostergios, Ana M. Molina, David M. Nanus, Himisha Beltran, Scott T. Tagawa. Variant allele frequency changes and treatment responses in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 426.