Case Report
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Apr 16, 2022; 10(11): 3461-3471
Published online Apr 16, 2022. doi: 10.12998/wjcc.v10.i11.3461
Circulating tumor DNA genomic profiling reveals the complicated olaparib-resistance mechanism in prostate cancer salvage therapy: A case report
Fang Yuan, Nan Liu, Ming-Zhen Yang, Xiao-Tian Zhang, Hong Luo, Hong Zhou
Fang Yuan, Nan Liu, Hong Luo, Hong Zhou, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400044, China
Ming-Zhen Yang, Department of Clinical Biochemistry, College of Medical Laboratory, Army Military Medical University, Chongqing 400038, China
Xiao-Tian Zhang, Department of Medicine, BGI Genomics, Shenzhen 518083, Guangdong Province, China
Author contributions: Yuan F, Liu N and Yang MZ collected the patient’s clinical data and drafted the paper; Yuan F and Luo H provided the patient’s clinical treatment; Zhang XT performed the molecular genetic studies; Zhou H designed and coordinated the study and participated in preparation of the draft; all authors read and approved the final manuscript.
Supported by the Natural Science Foundation of Chongqing, No. cstc2018jcyjAX0781; the Major Project of Chongqing Health Committee, No. cstc2016 shmszx130033031; the National Natural Science Foundation of China, No. 81302316; and the Chongqing technological innovation and application development - Major theme projects, No. cstc2019jscx-fxydx0008.
Informed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Hong Zhou, MD, Professor, Surgical Oncologist, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, No. 181 Hanyu Road, Shapingba, Chongqing 400044, China. zhouhongcqch@126.com
Received: November 27, 2020
Peer-review started: November 30, 2020
First decision: September 28, 2021
Revised: October 12, 2021
Accepted: February 25, 2022
Article in press: February 25, 2022
Published online: April 16, 2022
Abstract
BACKGROUND

The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib has displayed superior clinical effect in metastatic castration-resistant prostate cancer (mCRPC) patients with the homologous recombination repair (HRR) genes mutations. However, when a patient’s tumor tissue volume is insufficient for genomic profiling of HRR gene mutations, circulating tumor DNA (ctDNA) may be useful in helping to determine and monitor the efficacy of olaparib, as well as in abiraterone-combination treatment, and for understanding any resistance mechanism related to such mutations.

CASE SUMMARY

A 61-year-old man who was diagnosed with metastatic prostate adenocarcinoma was initially hormone sensitivity, showing high Gleason score (5 + 5 = 10) and absolute positive rate (14/14 biopsied specimens). Following failure of several standard therapies, the patient progressed to mCRPC. Surprisingly, the patient showed good response to olaparib-abiraterone-prednisone combination treatment (an androgen-deprivation therapy, provided as the ‘final choice’ in China). Serum total prostate-specific antigen (TPSA) level reduced and symptoms remitted for 4 months. However, thereafter, serum TPSA levels began slowly increasing, indicating development of olaparib resistance. Subsequent comprehensive genomic profiling of ctDNA, screening 508 cancer-related genes by next-generation sequencing, identified 10 somatic variants as well as 3 copy number alterations. Two identified reverse missense mutations in partner and localizer of BRCA2 (PALB2) may have recovered the reading frame, restoring function of the primary germline PALB2 mutation and causing resistance to the PARP inhibitor olaparib.

CONCLUSION

Reverse mutations in PALB2, discovered via genomic profiling of ctDNA, may represent a potential resistance mechanism against olaparib in mCRPC.

Keywords: mCRPC, Olaparib, Circulating tumor DNA, Partner and localizer of BRCA2, Resistance mechanism, Reverse missense mutations

Core Tip: This case report describes the poly (ADP-ribose) polymerase inhibitor olaparib treatment response in a patient with metastatic castration-resistant prostate cancer (mCRPC). The patient’s course of response to ‘final choice’ therapy (olaparib-abiraterone-prednisone combination treatment), consisting of serum total prostate-specific antigen (TPSA) level reduction and symptom remission for 4 months followed by TPSA rise, prompted comprehensive genomic profiling of circulating tumor (ct)DNA, which revealed reverse missense mutations in the partner and localizer of BRCA2 gene. Timely multigene testing by ctDNA, especially in mCRPC, can determine the most appropriate and accurate therapeutic approach and explore the resistance mechanism.