Homologous Recombination and Mismatch Repair Assessment in Men With Advanced Prostate Cancer: A Cross-Sectional Study From a Center in Mexico City

INTRODUCTION

In 2022, prostate cancer was estimated to be the most diagnosed malignancy among men in Mexico, accounting for 26,565 new cases and 7358 deaths.¹ Mexican men with prostate cancer experience significant disparities in access to advanced health care services, as reflected in the lower overall survival (OS) rates observed among individuals living in highly marginalized areas.² Moreover, prostate cancer mortality rates in Latin America are projected to increase, driven by changes in population demographics and growth.³

Patients with prostate cancer at elevated risk of progression and mortality, such as those with high- or very high-risk localized disease and metastatic disease, require genetic cancer risk assessment (GCRA) as part of their comprehensive management.^4-6 This highlights the critical need to expand GCRA services and improve access to molecular testing in developing countries.^7,8 Although most cases of prostate cancer are sporadic and considered multifactorial, germline variants in prostate cancer susceptibility genes with autosomal dominant inheritance have been identified. However, family history of cancer and age at prostate cancer diagnosis have not proven to be reliable predictors of germline pathogenic and likely pathogenic variant (PV) carriers.⁹ In contrast, disease stage has been a more accurate predictor. In studies that included mostly White patients, the prevalence of germline PVs among patients with localized disease has been reported as 4.6%,¹⁰ increasing to 11.8% in those with metastatic disease.¹¹ This contrasts with 4.2% reported by the PROSPECT trial (NCT01322490), which included men from 11 countries in Latin America and the Caribbean.¹²

After the discovery of androgen deprivation therapy, it took decades to identify newer effective drugs for the treatment of metastatic prostate cancer.¹³ The therapeutic landscape has since evolved to include next-generation taxanes, androgen receptor pathway inhibitors (ARPIs), radioligands, and poly (ADP-ribose) polymerase inhibitors (PARPis).

Several phase 3 clinical trials have addressed the role of PARPis in metastatic castration-resistant prostate cancer (CRPC). In the setting of progression after ARPIs, olaparib in the PROfound trial (NCT02987543) demonstrated improvements in progression-free survival (PFS) and OS compared with the control,¹⁴ while rucaparib in the TRITON3 trial (NCT02975934) has shown benefits in PFS compared with second ARPI or docetaxel in patients with metastatic CRPC; however, the trial did not demonstrate an improvement in OS.^15,16 Other trials have explored the use of PARPis in combination with ARPIs as first-line therapy for metastatic CRPC. Notable studies include PROpel (NCT03732820; olaparib + abiraterone), MAGNITUDE (NCT03748641; niraparib + abiraterone), and TALAPRO-2 (NCT03395197; talazoparib + enzalutamide), all of which have demonstrated benefits in PFS, and the latter recently demonstrated OS benefit.^17-20 Despite these advances, most clinical trials lacked participating centers in Latin America and had limited representation of Hispanic/Latino populations. Consequently, the findings may not be fully applicable to underrepresented groups with diverse ancestries and distinct genetic variant distributions. Few studies have reported the frequency of somatic and/or germline mutations in Latin America for men with prostate cancer, indicating limitations and barriers for the interpretation of the genomic landscape of this disease. For instance, results are heterogeneous due to a lack of unified reference criteria for GCRA in our population, different molecular testing methods based on resources, lack of specialized biobank technologies for tissue preservation, limited co-testing, and, most importantly, ancestry differences between countries.¹²

Moreover, mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) prostate cancer is observed in approximately 3% of cases.²¹ Nonetheless, in a cohort of 692 patients with metastatic prostate cancer, PVs in genes associated with Lynch syndrome accounted for approximately 4% of all hereditary prostate cancers, predominantly involving MSH2 and MSH6.¹¹ This is especially relevant as pembrolizumab is approved for dMMR/MSI-H metastatic CRPC and is a novel targeted therapy for this population.²²

This study aims to characterize the frequency and spectrum of somatic and germline PVs in 15 homologous recombination repair (HRR) pathway genes and TP53 in a cohort of Mexican patients with advanced prostate cancer treated at a referral genitourinary oncology clinic in Mexico City. A secondary objective was to describe the frequency of MMR-deficient tumors using universal screening with immunohistochemistry (IHC) on tumor tissue, to identify individuals at risk for Lynch syndrome.

Patients and Methods

Study Design and Population

We conducted a cross-sectional study including Mexican men 18 years or older with histologically confirmed stage IV prostate cancer who were treated at the Uro-Oncology Clinic of the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City. Universal testing at the clinic was performed irrespective of family history or castration-resistant status and included all patients with high- or very high–risk localized disease or metastatic prostate cancer. Patients with localized disease or without available tumor tissue and those with unsuccessful liquid biopsy results were excluded from this analysis. The study protocol was approved by the local institutional and ethics review board in April 2024 (code HEM-4993-24-25-1), aligning with the Declaration of Helsinki and the Strengthening the Reporting of Observational Studies in Epidemiology or STROBE recommendations for observational studies.Clinical and pathological characteristics were obtained from the medical records, including age at prostate cancer diagnosis, Gleason score, risk stratification according to the LATITUDE (NCT01715285) criteria,²³ tumor volume based on the CHAARTED trial (NCT00309985),²⁴ sites of metastasis, and ECOG performance status.

Molecular Analysis and Variant Characterization

Somatic genetic analysis was performed on paraffin-embedded tumor tissue samples, with DNA extracted using the AmoyDx kit from AstraZeneca. The analysis targeted the coding regions and exon-intron junctions of HRR-related genes included in the PROfound study—BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A,, RAD51B, RAD51C, RAD51D, RAD54L—along with TP53.¹⁴ In patients without available or nonviable tumor tissue, liquid biopsy testing was performed. The test was conducted on cell-free DNA (cfDNA) isolated from blood plasma, using unique molecular identifier–based target enrichment and sequencing with a custom capture kit, targeting the same previously listed genes. The limit of detection for somatic variants was 0.5% for single-nucleotide variants and short indels.

Following GCRA, peripheral blood samples were used for germline genetic testing. The coding regions and intron/exon junctions were analyzed using a capture enrichment-based assay with the Hereditary Risk Sequencing kit, followed by next-generation sequencing (NGS) on the MiSeq platform (Illumina). The germline panel included the following genes: BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L, and TP53. Noncoding regions (eg, deep introns) were not analyzed. Bioinformatic analysis was performed using the Sophia Genetics platform.

IHC for MMR proteins (MLH1, PMS2, MSH2, and MSH6) was performed on tumor tissue. In cases where tumors showed deficiency in 1 or more repair proteins, germline NGS was performed for MLH1,PMS2,MSH2, and MSH6.

Variant classification was based on the consensus criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, and on the guidelines of the International Agency for Research on Cancer (IARC).

DNA sequence variants were classified into 1 of 5 categories: benign (BV), likely benign (LBV), variant of uncertain significance (VUS), likely pathogenic (LPV), or pathogenic (PV). VUS were reported but not considered actionable results. For this analysis, only PV and LPV were deemed actionable.

Statistical Analysis

Descriptive statistics were calculated using frequencies and proportions for categorical variables, and median and range for quantitative variables. The Mann-Whitney U test and χ² test were used to examine differences in continuous and categorical variables between groups (HRR vs non-HRR), respectively. Statistical significance was defined as a 2-sided P-value under .05. A univariate analysis was conducted to identify variables associated with HRR alterations. This analysis was performed using the IBM SPSS Statistics 27.0.1.0 software.

RESULTS

Population

From July 2022 to September 2024, a total of 243 patients diagnosed with metastatic prostate cancer were identified. Among them, 212 provided informed consent for molecular analysis. However, 26 patients were excluded due to inadequate NGS results from tumor tissue or liquid biopsy. This study reports on the 186 patients who were successfully sequenced (Figure 1).

Across the entire cohort, the median age at diagnosis was 68 years (range, 41-90). Of these patients, 52.7% presented with de novo metastatic disease, 23.1% had high-risk disease, 25.8% had high-volume disease, and 35.5% were in the metastatic CRPC stage. Most patients self-identified as of mestizo-Mexican ancestry (96.2%) (Table 1). The most common treatment in metastatic hormone-sensitive prostate cancer (HSPC) was androgen deprivation therapy (ADT), followed by ADT plus ARPI. ADT plus ARPI was the most commonly used intervention in the castration-resistant scenario, and PARPis were used in 2 cases (Table 2).

Somatic Genomic Analysis for HRR genes

Somatic PVs in 1 or more of the 15 prespecified HRR genes were detected in 45 of 186 patients (24.2%). Overall, 52 somatic PVs in HRR genes were identified: 17 (32.7%) in ATM, 8 (15.4%) in PALB2, 7 (13.4%) in CHEK2, 6 (11.5%) in BRCA2, 5 (9.6%) in BARD1, 3 (5.7%) in RAD51B, 2 (3.8%) in BRCA1, 2 (3.8%) in BRIP1, 1 (1.9%) in FANCL, and 1 (1.9%) in RAD51D. Co-occurring somatic PVs in 2 or more HRR genes were identified in 6 cases (3.2%) (Figure 2).

No statistically significant differences were identified between individuals with HRR-positive and HRR-negative tumors in terms of age at diagnosis, de novo metastatic disease, high-risk disease, high-volume disease, the proportion of patients with metastatic CRPC, or family history of cancer (Table 1).

Germline Genetic Testing

Of the 186 individuals included, 101 (54.3%) completed germline genetic testing. Of these 101 probands, 12 (11.8%) were identified as carriers of PVs. A total of 12 germline PVs were detected: 3 (25.0%) in ATM, 3 (25.0%) in CHEK2, 1 (8.3%) in BARD1, 1 (8.3%) in BRCA2, 1 (8.3%) in BRIP1, 1 (8.3%) in FANCL, 1 (8.3%)in PPP2R2A, and 1 (8.3%)in TP53. One patient carried 2 germline PVs: ATM and PPP2R2A (Figure 3).

As expected, a greater proportion of carriers of germline PVs was documented among patients with HRR-positive tumors compared with those with HRR-negative tumors (28.6% vs 4.1%; P = .001).

Among the 8 patients with HRR-positive tumors who also carried a germline PV, co-testing yielded concordant results in 6 cases: 2 CHEK2, 1 ATM,
1 BRCA2, 1 BARD1, and 1 FANCL.

In 5 cases, somatic and germline testing results were discordant. One patient harbored somatic PVs in CHEK2 and TP53, while germline PVs were identified in ATM and PPP2R2A. Another patient harbored a somatic PV in CHEK2 and a germline PV in ATM. Additionally, 3 patients with HRR-negative tumors were found to carry germline PVs in ATM, BRIP1, and TP53, each with a single variant. The univariate analysis did not identify any statistically significant variables associated with an increased risk of HRR alterations.

Molecular findings in TP53

Of the 186 patients, 11 (5.9%) had tumors with PVs in TP53 without coexisting variants in HRR genes. Three out of 45 patients (6.7%) with HRR-positive tumors also harbored a somatic PV in TP53.

Only 1 patient, 0.9% of those who underwent germline testing, was identified carrying a germline PV in TP53, confirming a diagnosis of Li-Fraumeni syndrome. This individual presented with HRR-negative, TP53-mutant prostate cancer with neuroendocrine differentiation at diagnosis.

Variants of uncertain significance

VUSs in HRR genes were detected in tumor DNA analysis of 47 individuals (25.3%), with a total of 63 somatic VUSs identified. The frequency of somatic VUSs in TP53 was 1.2% (n = 1/186) (Figure 4A). In addition, 13 (12.9%) of 101 individuals harbored at least 1 germline VUS, for a total of 16. No germline VUSs were identified in TP53 (Figure 4B).

Mismatch Repair Analysis with IHC and NGS

IHC results for MMR proteins (MLH1, PMS2, MSH2, and MSH6) were available in 140 patients. MMR-deficient tumors were detected in 3 patients (2.1%), all of whom exhibited a deficiency in the MSH2-MSH6 complex. As part of the comprehensive GCRA, germline NGS analysis of MSH2 and MSH6 was conducted. None of these 3 patients was diagnosed with Lynch syndrome.

The 3 patients with MMR-deficient metastatic prostate cancer were in the castration-resistant stage, and at the data cutoff, none had received PD-1 blockade.

DISCUSSION

The frequency of PVs in HRR genes identified through tumor DNA analysis in this cohort of Mexican men with advanced prostate cancer was 24.2%, which is comparable to the range of 20% to 30% reported in other populations,^25,26 but higher than a previous cohort from Latin America (13.18%).^7,12 Only 54.3% of the cohort underwent germline genetic testing, primarily due to restricted access after the sponsor discontinued coverage, underscoring the limited accessibility in our setting. This issue is not unique to our institution, as real-world data consistently reveal suboptimal access to and utilization of GCRA among patients with advanced prostate cancer.²⁶ Although genetic testing rates have improved since the approval of PARPis for metastatic CRPC,²⁷ progress could be slower in low- and middle-income countries due to limited resources. In our study, the prevalence of germline PVs was 11.8%, aligning with results from a multicenter cohort of American and British men with metastatic prostate cancer.¹¹ This contrasts with 2.0% found in a previous cohort at our center, which included patients with prostate cancer meeting criteria for GCRA (45% with de novo metastatic disease and 26% with high-risk localized disease).²⁸ These differences may be explained by the clinical stage of the patients in each cohort and potentially by referral bias, as in the present study, patients with HRR-positive tumors were more frequently referred for GCRA (28 of 45 [62.2%] vs 73 of 141 [51.7%] patients with HRR-positive and HRR-negative tumors, respectively).

Among the 45 patients with HRR-positive tumors, only 2 received olaparib. However, in the metastatic CRPC setting, this represented 12.5% (n = 2 of 16 eligible patients). This underscores that even after trying to implement comprehensive genetic testing in resource-limited settings, access remains limited, consistent with real-world evidence.²⁹ The low use of PARPi in our setting seems even more pronounced when considering the approval for “all comers” patients, where individuals with metastatic CRPC may qualify regardless of their HRR status. The main reasons for this gap include limited access to PARPis within the Mexican health care system and the fact that some patients underwent genetic testing in later treatment lines, often when their performance status had declined.

When comparing our cohort to a contemporary study of Spanish patients, both populations showed a similar prevalence of PVs (24.2% vs 28.6%). Notably, our cohort exhibited a substantially lower rate of high-volume metastatic disease (25.8% vs 55.0%). Despite this difference in tumor burden, the frequency of PVs in HRR genes remained comparable between high- and low-volume groups within each cohort (20.8% vs 25.3% in our cohort, and 28.1% vs 28.8% in the Spanish cohort). These findings suggest that tumor burden is not a predictor of PV carriage. Rather, metastatic status appears to be the relevant determinant, reinforcing the value of universal genetic testing in patients with metastatic disease regardless of volume.³⁰

Although in our study, NGS was primarily conducted on prostate biopsy tissue or liquid biopsy samples during the metastatic HSPC stage, HRR gene alterations are well recognized as early events in prostate cancer. This is evidenced by the high concordance of PVs identified in paired primary tumor tissue and metastatic tissue or cfDNA upon progression to metastatic CRPC.^31-33 Understanding this principle highlights the value of identifying somatic PVs from primary tumor and metastatic biopsy tissue in the metastatic HSPC setting, enabling informed treatment planning for anticipated progression to the metastatic CRPC stage.

In our cohort, the prevalence of somatic and germline VUSs was 25.3% and 12.9%, respectively. The identification of a VUS poses a significant challenge for clinicians. The available evidence for VUSs is inadequate to establish their role as disease-causing variants at the time of classification. Consequently, VUSs should not be used as a basis for medical management decisions.³⁴ In such cases, it is essential to refer patients to GCRA specialists for ongoing follow-up and potential reclassification of VUSs. For patients with a history of prostate cancer under surveillance or asymptomatic germline VUS carriers, annual reassessment is recommended, as reclassification to a PV or LPV could influence screening strategies and cascade testing recommendations. Conversely, reclassification to BV or LBV may justify discontinuing follow-up by GCRA services.³⁵ For patients who have metastatic disease on active treatment, it would be reasonable to reassess whether the VUS has been reclassified at shorter intervals, particularly when a change in treatment line is being considered. Continuous follow-up is crucial, as the reclassification of a VUS to PV or LPV could render the patient eligible for PARPi therapy. Although most VUSs are reclassified as BV or LBV, these rates are higher among underrepresented populations, including Hispanic individuals.³⁶ From a global oncology perspective, a VUS result poses a significant challenge to health care systems in resource-constrained settings due to the need for a multidisciplinary approach, long-term follow-up by trained physicians, and the establishment of a national public database. To address these disparities, future strategies should focus not only on expanding access to genetic testing but also on promoting cascade testing, reevaluating VUS carriers, and implementing a national reporting system to track and monitor these variants, ensuring reliable, up-to-date data for our population.

In 5.9% of tumors, we identified PVs in TP53 without coexisting PVs in HRR genes, and 6.7% of HRR-positive tumors also harbored a PV in TP53. In comparison with our data, the prevalence of somatic TP53 mutations in Mexican men appears to be lower than that reported in other populations. Based on data extracted from the registry of the American Association for Cancer Research Project GENIE (Genomics Evidence Neoplasia Information Exchange), among patients with metastatic prostate cancer, somatic TP53 mutations were more common in Asian men compared with White or Black men (62.0%, 36.4%, and 22.5%, respectively).³⁷ This is important as real-world evidence from Guardian Research Network indicates that patients with TP53, RB1, and PTEN-mutated prostate cancer have shorter survival compared with those without these biomarkers.³⁸ The case of TP53 exemplifies how clinically significant alterations may occur at different frequencies across individuals from different ancestral backgrounds, underscoring the importance of including diverse populations in clinical trials. However, in our cohort, only 1 patient (0.9%) tested positive for a germline PV in TP53. This is consistent with reported frequencies in other cohorts, where germline TP53 PVs occur at approximately 0.66%.^9,39

Clonal hematopoiesis of indeterminate potential (CHIP) is a condition in which blood cells acquire somatic mutations, leading to clonal expansion of hematopoietic stem cells without meeting criteria for hematologic malignancy. These mutations often occur in cancer-related genes, such as TP53.⁴⁰ In some of our patients, NGS was performed on cfDNA obtained from peripheral blood samples, raising the possibility that CHIP contributed to a proportion of the PVs identified in TP53. Additionally, individuals with metastatic prostate cancer have risk factors for CHIP, such as older age and exposure to multiple lines of chemotherapy.⁴¹ Studies suggest that CHIP may interfere with plasma cfDNA testing in patients with metastatic prostate cancer, impacting PVs identification in TP53 and HRR genes. This could lead to misdiagnosis and overtreatment with PARPis.⁴² Thus, careful evaluation of NGS results, including variant allele frequency (VAF), is essential. VAF represents the fraction of variant sequencing reads within a genetic locus and provides insights into tumor heterogeneity. Additionally, VAF can help differentiate between driver and passenger mutations and indicate whether a PV is inherited. As such, VAF plays a crucial role in identifying the most relevant cancer cell populations for targeted treatment.²¹ For instance, in epithelial ovarian cancer, a study showed that patients with somatic PVs in BRCA1 or BRCA2 and a high VAF exhibit improved responses to PARPi treatment.⁴³ However, there is a lack of validated VAF thresholds for identifying patients with metastatic CRPC eligible for PARPi therapy, presenting an opportunity for future research to refine patient selection criteria.

In our cohort, MMR deficiency was detected in 2.1% of tumors analyzed by IHC, but no cases of Lynch syndrome were identified. Similarly, in a cohort of 1033 patients with prostate cancer, 3.1% had dMMR/MSI-H tumors, of which 21.9% were caused by Lynch syndrome.⁴⁴ The absence of Lynch syndrome cases in our cohort may be due to the limited sample size.

With immunotherapy approved for dMMR/MSI-H solid tumors, identifying these biomarkers in metastatic CRPC has become increasingly important. The phase 2 KEYNOTE-199 study (NCT02787005) included patients with metastatic CRPC, unselected for dMMR/MSI-H status, who had previously received docetaxel and targeted endocrine therapy. Among those with measurable disease, pembrolizumab showed low response rates of 5% in PD-L1–positive and 3% in PD-L1–negative cohorts.²² In contrast, though uncommon and with limited clinical experience, studies focusing on patients with dMMR/MSI-H or tumor mutational burden–high metastatic CRPC have reported objective response rates of approximately 50%,^45,46 underscoring the importance of more precise candidate selection for this treatment strategy. Expanding immunotherapy access could improve outcomes in dMMR/MSI-H metastatic CRPC, providing an alternative for patients with limited treatment options. However, high costs remain a barrier in resource-limited settings.

We should advocate for the implementation of universal germline genetic testing paired with tumor profiling in men with metastatic prostate cancer across all ethnicities and ancestries, as it increases the detection of clinically actionable variants that might otherwise go unnoticed if selection criteria were based solely on clinical stage or family history.^47,48 However, universal testing is expected to increase the number of patients referred to GCRA. To address this, expanding the number of specialists in GCRA and implementing innovative strategies, such as telemedicine services, will be essential to enhance access to pre- and posttest counseling in Latin America.⁴⁹ Nevertheless, several uncertainties remain regarding the implementation of GCRA in our region, including the selection of genes to analyze, patient adherence to follow-up, proper integration of genetic panel reports into medical records, and education on non-discrimination and genetic information protection, as required by Mexico’s General Health Law.

We acknowledge several limitations of this study. This was a single-center study conducted in Mexico City. In addition, germline testing was not uniformly performed across the cohort, introducing potential selection bias as previously discussed. Furthermore, the retrospective nature precludes full control over the testing across all patients. As a result, it may not accurately reflect the true prevalence and mutational landscape of HRR deficiency and MMR deficiency in Mexican men with metastatic prostate cancer. However, to our knowledge, this is the first study to address the prevalence of both somatic and germline alterations in the HRR and MMR pathways among men with metastatic prostate cancer.

CONCLUSION

The molecular profile of mestizo-Mexican individuals with metastatic prostate cancer showed a prevalence of somatic and germline PVs comparable to those of other populations, with a notable frequency of variants in ATM, PALB2, and CHEK2. The low proportion of dMMR tumors aligns with previous reports, while the lower frequency of somatic TP53 PVs suggests a distinct molecular background in this population. To our knowledge, this is the first comprehensive study of advanced prostate cancer in Mexico, highlighting the importance of expanding access to NGS in tumor DNA, germline genetic testing, and targeted therapies to improve patient outcomes.

Source of Support

Somatic genetic testing and two-thirds of the germline genetic testing were performed with funding provided by AstraZeneca as part of a support program for genetic assessment for men with advanced prostate cancer. One-third of the germline genetic testing was performed through the GRACIAS project, with support from Breast Cancer Research Foundation grants 23-210 and 24-210 (J. Weitzel).

Corresponding Author

Maria T. Bourlon, MD, MSc, FASCO
Twitter: @BourlonMaite
email: maitebourlon@gmail.com

Author Contributions

Conception and design: José Luis Rodríguez Olivares, Mauricio Mora Pineda, Evelyn Beas Lozano, Yuly A. Remolina Bonilla, Yanin Chavarri-Guerra, Armando Gamboa-Dominguez, Pedro Barata, Maria T. Bourlon

Financial support: Maria T. Bourlon

Administrative support: Maria T. Bourlon

Provision of study materials or patients: Maria T. Bourlon, Yanin Chavarri-Guerra, Jeffrey N. Weitzel, Armando Gamboa-Dominguez

Collection and assembly of data: Mauricio Mora Pineda, Alec Seidman-Sorsby, Evelyn Beas Lozano, Yuly A. Remolina Bonilla, Jeffrey N. Weitzel, Pedro Barata, Yanin Chávarri-Guerra, Maria T. Bourlon

Data analysis and interpretation: José Luis Rodríguez Olivares, Evelyn Beas Lozano, Yuly A. Remolina Bonilla, Mauricio Mora Pineda, Pedro Barata

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

References

1. Ferlay J, Ervik M, Lam F, et al. Global Cancer Observatory: cancer Today. IARC; 2024. Accessed April 8, 2025. https://gco.iarc.who.int/media/globocan/factsheets/populations/900-world-fact-sheet.pdf
2. Torres-Sánchez L, Hernández-Pérez JG, Escamilla-Nuñez C, et al. Disparities on prostate cancer survival in Mexico: a retrospective cohort study. Salud Publica Mex. 2023;65(3):236-244. doi:10.21149/14266
3. Torres-Roman JS, Valcarcel B, Arce-Huamani MA, et al. Prostate cancer in Latin America and the Caribbean: mortality trends from 1997 to 2017 and predictions to 2030. Salud Publica Mex. 2024;66(3):226-235. doi:10.21149/15463
4. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 1.2025. Accessed May 19, 2025. https://www.nccn.org/guidelines/guidelines-detail
5. Yu EY, Rumble RB, Agarwal N, et al. Germline and somatic genomic testing for metastatic prostate cancer: ASCO guideline. J Clin Oncol. 2025;43(6):748-758.. doi:10.1200/JCO-24-02608
6. Stopsack KH, Vijai J, Conry M, et al. Germline DNA damage repair variants and prognosis of patients with high-risk or metastatic prostate cancer. Clin Cancer Res. 2025;31(1):122-129. doi:10.1158/1078-0432.CCR-24-2483
7. Angel M, Freile B, Rodriguez A, et al. Genomic landscape in prostate cancer in a Latin American population. JCO Glob Oncol. 2024;10:e2400072. doi:10.1200/GO.24.00d072
8. Blazer KR, Chavarri-Guerra Y, Villarreal Garza C, et al. Development and pilot implementation of the Genomic Risk Assessment for Cancer Implementation and Sustainment (GRACIAS) intervention in Mexico. JCO Glob Oncol. 2021;7:992-1002. doi:10.1200/GO.20.00587
9. Nicolosi P, Ledet E, Yang S, et al. Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines. JAMA Oncol. 2019;5(4):523-528. doi:10.1001/jamaoncol.2018.6760
10. The Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell. 2015;163(4):1011-1025. doi:10.1016/j.cell.2015.10.025
11. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-453. doi:10.1056/nejmoa1603144
12. Manneh R, Verson CA, Martin A, et al. Prospective study of homologous recombination repair gene mutation prevalence in patients with advanced prostate cancer from Latin America: challenges and future approaches. JCO Precis Oncol. 2024;8:e2300628. doi:10.1200/po.23.00628
13. Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J Clin. 1972;22(4):232-240. doi:10.3322/canjclin.22.4.232
14. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091-2102. doi:10.1056/nejmoa1911440
15. Fizazi K, Piulats JM, Reaume MN, et al. Rucaparib or physician's choice in metastatic prostate cancer. N Engl J Med. 2023;388(8):719-732. doi:10.1056/nejmoa2214676
16. Bryce AH, McDermott RS, Piulats JM, et al. Rucaparib vs docetaxel (DTX) or second-generation androgen pathway inhibitor (ARPI) therapy for metastatic castration-resistant prostate cancer (mCRPC): TRITON3 final overall survival (OS) and safety. J Clin Oncol. 2025;43(suppl 5):155. doi:10.1200/JCO.2025.43.5_suppl.155
17. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid. 2022;1(9):EVIDoa2200043. doi:10.1056/EVIDoa2200043
18. Chi KN, Sandhu S, Smith MR, et al. Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial. Ann Oncol. 2023;34(9):772-782. doi:10.1016/j.annonc.2023.06.009
19. Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. 2023;402(10398):291-303. doi:10.1016/S0140-6736(23)01055-3
20. Agarwal N, Azad A, Carles J, et al. Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line treatment in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial. J Clin Oncol. 2025;43(suppl 5):LBA18. doi:10.1200/JCO.2025.43.5_suppl.LBA18
21. Boscolo Bielo L, Trapani D, Repetto M, et al. Variant allele frequency: a decision-making tool in precision oncology? Trends Cancer. 2023;9(12):1058-1068. doi:10.1016/j.trecan.2023.08.011
22. Antonarakis ES, Piulats JM, Gross-Goupil M, et al. Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 study. J Clin Oncol. 2020;38(5):395-405. doi:10.1200/JCO.19.01638
23. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352-360. doi:10.1056/nejmoa1704174
24. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737-746. doi:10.1056/nejmoa1503747
25. Shui IM, Burcu M, Shao C, et al. Real-world prevalence of homologous recombination repair mutations in advanced prostate cancer: an analysis of two clinico-genomic databases. Prostate Cancer Prostatic Dis. 2024;27(4):728-735. doi:10.1038/s41391-023-00764-1
26. Shore N, Ionescu-Ittu R, Yang L, et al. Real-world genetic testing patterns in metastatic castration-resistant prostate cancer. Future Oncol. 2021;17(22):2907-2921. doi:10.2217/fon-2021-0153
27. Barata PC, Assayag J, Li B, Siu G, Niyazov A. Genetic testing in men with metastatic castration-resistant prostate cancer. JAMA Oncol. 2024;10(7):975-977. doi:10.1001/jamaoncol.2024.0851
28. Chávarri-Guerra Y, Bourlon MT, Rodríguez-Olivares JL, et al. Germline DNA repair genes pathogenic variants among Mexican patients with prostate cancer. Clin Genitourin Cancer. 2023;21(5):569-573. doi:10.1016/j.clgc.2023.05.012
29. Shore ND, Vasudevan A, Li J, et al. Real-world clinical practice gaps in timely homologous recombination repair gene mutation (HRRm) testing and poly (ADP-ribose) polymerase inhibitor (PARPi) treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2025;43(suppl 5):85. doi:10.1200/JCO.2025.43.5_suppl.85
30. Olmos D, Lorente D, Jambrina A, et al. BRCA1/2 and homologous recombination repair alterations in high- and low-volume metastatic hormone-sensitive prostate cancer: prevalence and impact on outcomes. Ann Oncol. 2025;36(10):1190-1202. doi:10.1016/j.annonc.2025.05.534
31. Mateo J, Seed G, Bertan C, et al. Genomics of lethal prostate cancer at diagnosis and castration resistance. J Clin Invest. 2020;130(4):1743-1751. doi:10.1172/JCI132031
32. Warner E, Herberts C, Fu S, et al. BRCA2, ATM, and CDK12 defects differentially shape prostate tumor driver genomics and clinical aggression. Clin Cancer Res. 2021;27(6):1650-1662. doi:10.1158/1078-0432.CCR-20-3708
33. Schweizer MT, Sivakumar S, Tukachinsky H, et al. Concordance of DNA repair gene mutations in paired primary prostate cancer samples and metastatic tissue or cell-free DNA. JAMA Oncol. 2021;7(9):1378-1382. doi:10.1001/jamaoncol.2021.2350
34. Nicolosi P, Heald B, Esplin ED. What is a variant of uncertain significance in genetic testing? Eur Urol Focus. 2022;8(3):654-656. doi:10.1016/j.euf.2022.03.018
35. Walsh N, Cooper A, Dockery A, O'Byrne JJ. Variant reclassification and clinical implications. J Med Genet. 2024;61(3):207-211. doi:10.1136/jmg-2023-109488
36. Kobayashi Y, Chen E, Facio FM, et al. Clinical variant reclassification in hereditary disease genetic testing. JAMA Netw Open. 2024;7(11):e2444526. doi:10.1001/jamanetworkopen.2024.44526
37. Mahal BA, Alshalalfa M, Kensler KH, et al. Racial differences in genomic profiling of prostate cancer. N Engl J Med. 2020;383(11):1083-1085. doi:10.1056/NEJMc2000069
38. Arfat Ganiyani M, Prabhakar P, Aman Khosla A, et al. Impact of TP53, RB1, and PTEN mutations on overall survival in metastatic prostate cancer: a multi-center study via the Guardian Research Network. J Clin Oncol. 2025;43(suppl 5):82. doi:10.1200/JCO.2024.42.4_suppl.82
39. Maxwell KN, Cheng HH, Powers J, et al. Inherited TP53 variants and risk of prostate cancer. Eur Urol. 2022;81(3):243-250. doi:10.1016/j.eururo.2021.10.036
40. Castillo D, Yuan TA, Nehoray B, et al. Clonal hematopoiesis and mosaicism revealed by a multi-tissue analysis of constitutional TP53 status. Cancer Epidemiol Biomarkers Prev. 2022;31(8):1621-1629. doi:10.1158/1055-9965.EPI-21-1296
41. Gondek LP. CHIP: is clonal hematopoiesis a surrogate for aging and other disease? Hematology Am Soc Hematol Educ Program. 2021;2021(1):384-389. doi:10.1182/hematology.2021000270
42. Jensen K, Konnick EQ, Schweizer MT, et al. Association of clonal hematopoiesis in DNA repair genes with prostate cancer plasma cell-free DNA testing interference. JAMA Oncol. 2021;7(1):107-110. doi:10.1001/jamaoncol.2020.5161
43. Grech CT, Pils D, Aust S, et al. Corrected allele frequency of BRCA1/2 mutations is an independent prognostic factor for treatment response to PARP-inhibitors in ovarian cancer patients. J Pers Med. 2022;12(9):1467. doi:10.3390/jpm12091467
44. Abida W, Cheng ML, Armenia J, et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol. 2019;5(4):471. doi:10.1001/jamaoncol.2018.5801
45. Barata P, Agarwal N, Nussenzveig R, et al. Clinical activity of pembrolizumab in metastatic prostate cancer with microsatellite instability high (MSI-H) detected by circulating tumor DNA. J Immunother Cancer. 2020;8(2):e001065. doi:10.1136/jitc-2020-001065
46. Zang PD, Chawla NS, Barragan-Carrillo R, et al. Tumor mutational burden in metastatic castration-resistant prostate cancer and response to checkpoint inhibition. JAMA Oncol. 2024;10(4):531. doi:10.1001/jamaoncol.2023.6817
47. Shore N, Gazi M, Pieczonka C, et al. Efficacy of National Comprehensive Cancer Network guidelines in identifying pathogenic germline variants among unselected patients with prostate cancer: the PROCLAIM trial. Eur Urol Oncol. 2023;6(5):477-483. doi:10.1016/j.euo.2023.07.008
48. Shore N, Armstrong AJ, Barata P, et al. Implementing and optimizing universal germline genetic testing for patients with prostate cancer in clinical practice. Urology. 2025;199:1-10. doi:10.1016/j.urology.2025.01.070
49. Chávarri-Guerra Y, Rodríguez-Olivares JL, Ramírez-González A, et al. Addressing the need for genetic cancer risk assessment in Mexico: from establishment of a formal program to delivery innovation and expansion. Genet Med Open. 2024;2(suppl 2):101874. doi:10.1016/j.gimo.2024.101874