Genetic testing for homologous recombination repair (HRR) in metastatic castration-resistant prostate cancer (mCRPC): challenges and solutions

Rodney J. Scott _, Anurag Mehta, Gabriel S. Macedo, Pavel S. Borisov, Ravindran Kanesvaran and Wafaa El Metnawy

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Oncotarget. 2021; 12:1600-1614. https://doi.org/10.18632/oncotarget.28015

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Rodney J. Scott1, Anurag Mehta2, Gabriel S. Macedo3, Pavel S. Borisov4, Ravindran Kanesvaran5 and Wafaa El Metnawy6

1 Laureate Professor, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia

2 Director, Department of Laboratory & Transfusion Services and Director Research, Rajiv Gandhi Cancer Institute, Delhi, India

3 Programa de Medicina Personalizada – Coordenador, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

4 Oncologist Urologist, FSBI “N.N. Petrov NMRC of Oncology” of the Ministry Healthcare of the Russian Federation, St Petersburg, Russia

5 Deputy Head and Senior Consultant, Division of Medical Oncology, National Cancer Centre Singapore, Singapore

6 Professor of Molecular Pathology, Oncology Center School of Medicine, Cairo University, Giza, Egypt

Correspondence to:

Rodney J. Scott,email: [email protected]

Keywords: metastatic castration-resistant prostate cancer; homologous recombination repair; next generation sequencing; genetic testing

Received: May 19, 2021     Accepted: June 14, 2021     Published: August 03, 2021

Copyright: © 2021 Scott et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Patients with metastatic castration-resistant prostate cancer (mCRPC) have an average survival of only 13 months. Identification of novel predictive and actionable biomarkers in the homologous recombination repair (HRR) pathway in up to a quarter of patients with mCRPC has led to the approval of targeted therapies like poly-ADP ribose polymerase inhibitors (PARPi), with the potential to improve survival outcomes. The approval of PARPi has led to guideline bodies such as the National Comprehensive Cancer Network (NCCN) to actively recommend germline and or somatic HRR gene panel testing to identify patients who will benefit from PARPi. However, there are several challenges as genetic testing is still at an early stage especially in low- and middle-income countries, with cost and availability being major impediments. In addition, there are issues such as choice of optimal tissue for genetic testing, archival, storage, retrieval of tissue blocks, interpretation and classification of variants in the HRR pathway, and the need for pretest and post-test genetic counseling. This review provides insights into the HRR gene mutations prevalent in mCRPC and the challenges for a more widespread gene testing to identify actionable germline pathogenic variants and somatic mutations in the HRR pathway, and proposes a clinical algorithm to enhance the efficiency of the gene testing process.

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