Academic Report for the Paper Titled “Prospective Study of Homologous Recombination Repair Gene Mutation Prevalence in Patients with Advanced Prostate Cancer from Latin America: Challenges and Future Approaches”

Background

Prostate cancer is one of the most common cancers among men in Latin America and the Caribbean (LAC). According to the 2020 Global Cancer Observations report (Globocan 2020), 214,522 new cases of prostate cancer were reported in the region, accounting for 15.2% of all cancers and making up a high 29.8% of male cancer cases. Although the incidence of prostate cancer in the LAC region (15.2%) is slightly lower than in North America (16.9%), the mortality rate is roughly 50% higher (15.3% versus 9.9%). Additionally, the aging rate of the LAC population is projected to be significantly faster than in North America, with a 156% increase in elderly population expected between 2019 and 2050, compared to 48% in North America. Given that prostate cancer incidence is closely associated with age, the rapidly aging population of the LAC region, along with poorer survival rates and higher healthcare costs, underscores the need for a better understanding and characterization of advanced prostate cancer in this region.

Research Origin

This research paper was written by Ray Manneh and other authors from various institutions, such as Sociedad de Oncología y Hematología del Cesar, Instituto Nacional de Medicina Genómica, Instituto Alexander Fleming, among others. The study was published on May 15, 2024, in the journal JCO Precision Oncology, DOI: https://doi.org/10.1200/po.23.00628.

Study Content

Objectives

The “Prospect” study aims to determine the prevalence of homologous recombination repair gene mutations (HRRm) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the LAC region and to describe the demographic and clinical characteristics of the participants. This is the first attempt to describe the HRRm prevalence in LAC prostate cancer patients.

Materials and Methods

This is a prospective, cross-sectional, multi-center study covering 11 cancer centers in seven countries in the LAC region. All participants provided informed consent and submitted blood samples for germline HRR mutation testing, and, if feasible, prostate cancer tissue samples for somatic HRR mutation testing. The study included participants confirmed to have mCRPC, aged 18 years or older. Participants were required to provide medical and demographic information and be able to provide blood and tissue samples. Patients with severe acute or chronic medical or psychiatric conditions that could increase the risk of research participation or interfere with test result interpretation were excluded.

Experimental Procedure

All blood and tissue samples were analyzed in local laboratories in Argentina and Brazil and a central laboratory in Mexico. The AmoyDx Halo-Shape Annealing and Defer-Ligation Enrichment (HANDLE) HRR Next Generation Sequencing panel was used to analyze somatic and germline mutations in blood and tissue. This included detecting single nucleotide variants (SNVs) and insertions and deletions (INDELs) in protein-coding regions and intron/exon boundaries across 25 HRR genes and additional regions.

Data Collection

The study complied with national health ministry regulations and the ethical principles of the Helsinki Declaration. Data processing followed good clinical practice and federal and local regulatory requirements. All source documents were completed by on-site personnel or research staff and signed by data collectors. All samples were labeled and transported per applicable local laws and regulations, following the manufacturer’s instructions for sample handling and transportation to ensure traceability throughout the process.

Results

From April 2021 to April 2022, the study screened 395 patients and enrolled 387. Almost 40% of the patients had a family history of cancer. Baseline surveys indicated a median age of participants at 70 years, with 94% at Eastern Cooperative Oncology Group (ECOG) stages 0-1. Among the study population, 151 patients (39%) had a family history of cancer, mostly first-degree relatives (120, accounting for 80%). Due to insufficient tissue samples, lack of tumor cells, and poor DNA quality, 79% of somatic HRR tests failed, making it impossible to assess the prevalence of somatic HRRm.

The overall prevalence of germline HRR gene mutations in the study was 4.2%, including mutations in CHEK2, ATM, BRCA2, BRIP1, RAD51B, BRCA1, and MRE11. The study did not find a significant association between baseline characteristics and germline HRR mutations.

The high rate of somatic HRRm test failures was identified as a major challenge, prompting the implementation of several improvement measures to enhance HRR testing and biomarker-based treatments for mCRPC patients in the LAC region.

Conclusion

This study demonstrates the prevalence of HRRm in mCRPC patients in the LAC region and indicates that the HRRm prevalence in this region is lower compared to North American and European populations. The high failure rate of somatic HRR testing needs further resolution to enhance HRR detection and the accessibility of biomarker-based treatments.

Study Highlights

1. First Attempt: This study is the first to describe the prevalence of HRRm in mCRPC patients in the LAC region, providing valuable baseline data for the region.
2. Baseline Characteristics: The study offers detailed descriptions of baseline characteristics such as family history, diagnosis time, and metastasis sites.
3. Failure Reasons for HRR Gene Mutation Testing: The study identified reasons for the high HRR testing failure rates, including inadequate DNA, lack of tumor cells, and poor DNA quality.
4. Follow-up Improvement Measures: Several improvement measures were proposed to address testing failures, aiming to improve HRR testing and the accessibility of biomarker-based therapy.

Significance and Value of the Study

This study holds significant scientific and practical value. Scientifically, it provides the first data on HRRm prevalence in mCRPC patients in the LAC region, filling a gap in regional research. Practically, it identifies existing obstacles in testing and treatment, laying the foundation for more effective detection and treatment strategies for mCRPC patients in the LAC region. The high test failure rate discovered during the study has prompted relevant parties to implement a series of improvement measures, such as training programs for pathologists on sample optimization and preservation and the promotion of liquid biopsy, which will help enhance detection and treatment levels for patients in the region.

Supplementary Content

1. Global Trends in Genetic Testing: Although the global rate of genetic testing is gradually increasing, the study found that over two-thirds of US patients had not undergone HRR testing. In contrast, the accessibility of genetic testing in the LAC region is evidently lower. This indicates that more resources and policy support are needed in the future to expand genetic testing coverage in various countries.
2. Ethical Considerations: The study strictly adhered to the ethical guidelines and laws mandated by various countries, obtaining approval from the ethics committees of relevant institutions, showing high standards of ethical and legal compliance in the research.

This study not only provides crucial data on genetic testing and treatment directions for mCRPC patients in the LAC region but also reveals existing challenges and future improvement directions, holding profound significance and value.