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HRR Mutation Testing in mPC

Progress in HRR testing for prostate cancer

Last updated:18th Jan 2025
Published:18th Jan 2025

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HRR mutation testing in prostate cancer can guide management decisions

Metastatic prostate cancer (mPC) is not curable and has a very poor prognosis – current 5-year survival rates are about 34%,1,2 and median survival in metastatic castration-resistant prostate cancer (mCRPC) is 13 months.3

One reason may be the high prevalence of pathogenic alterations in homologous recombination repair (HRR) genes, such as ATM, BRCA1/2, CDK3, CDK12, CHEK2, and HOXB13: 16% of men with PC and up to a third of men with mCRPC have ≥1 HRR mutation (HRRm) as shown in Figure 1, and around 13% have BRCA1/2 mutations.4 As well as increasing the risk of developing PC (7–26% of BRCA1 and 19–61% of BRCA2 mutation carriers are likely to develop PC by age 80, compared with around 10.6% of men in the general population), HRRm are associated with younger age at onset, more aggressive tumors, worse treatment response, shorter time to progression from metastatic castration-sensitive prostate cancer (mCSPC) to mCRPC, and worse overall survival.5-14

Pie chart showing HRR gene alteration prevalence in patients with mCRPC. Around 28% of patients had an HRR gene mutation.

Figure 1. Prevalence of HRR alterations in 2,792 patients with mCRPC enrolled in the PROfound trial15. HRR, homologous recombination repair; mCRPC, metastatic castration-resistant prostate cancer.

Fortunately, the treatment landscape is changing. The arrival of targeted therapies means that HRRm status can be used to guide treatment choice:

  • BRCA1/2, ATM, and PALB2 mutations are associated with positive response to poly (ADP-ribose) polymerase inhibitors (PARPi)16
  • CDK12 mutations are associated with low response to androgen receptor signaling pathway inhibitors (ARSIs), PARPi, PD-1 inhibitors, and docetaxel16,17

These findings highlight the importance of genetic testing in men with PC.

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References

  1. American Cancer Society, 2024. Cancer facts & figures. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2024/2024-cancer-facts-and-figures-acs.pdf
  2. Schostak, 2024. Practical guidance on establishing a molecular testing pathway for alterations in homologous recombination repair genes in clinical practice for patients with metastatic prostate cancer. https://www.doi.org/10.1016/j.euo.2023.08.004
  3. Aly, 2020. Survival in patients diagnosed with castration-resistant prostate cancer: a population-based observational study in Sweden. https://www.doi.org/10.1080/21681805.2020.1739139
  4. Dall'Era, 2020. Germline and somatic DNA repair gene alterations in prostate cancer. https://www.doi.org/10.1002/cncr.32908
  5. Bilen, 2024. Homologous recombination repair testing patterns and outcomes in mCRPC by alteration status and race. https://www.doi.org/10.2147/CEOR.S468680
  6. National Cancer Institute, 2024. BRCA gene changes: cancer risk and genetic testing. https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet
  7. Page, 2019. Interim results from the IMPACT study: Evidence for prostate-specific antigen screening in BRCA2 mutation carriers. https://www.doi.org/10.1016/j.eururo.2019.08.019
  8. Lee, 2022. The prognostic significance of homologous recombination repair pathway alterations in metastatic hormone sensitive prostate cancer. https://www.doi.org/10.1016/j.clgc.2022.06.016
  9. Shao, 2022. A systematic review and meta-analysis on the prognostic value of BRCA mutations, homologous recombination gene mutations, and homologous recombination deficiencies in cancer. https://www.doi.org/10.1155/2022/5830475
  10. Karlsson, 2021. Rare germline variants in ATM predispose to prostate cancer: A PRACTICAL consortium study. https://www.doi.org/10.1016/j.euo.2020.12.001
  11. Kafka, 2021. Recent insights on genetic testing in primary prostate cancer. https://www.doi.org/10.1007/s40291-021-00529-3
  12. Huang, 2022. Verification of cell cycle-associated cyclin-dependent kinases facilitated prostate cancer progression by integrated bioinformatic analysis and experimental validation. https://www.doi.org/10.1016/j.heliyon.2022.e10081
  13. Castro, 2023. P135 - Homologous recombination repair mutation (HRRm) testing patterns among men with metastatic castration-resistant prostate cancer (mCRPC): Interim results from a real-world (rw) study in Europe. https://www.doi.org/https://doi.org/10.1016/S2666-1683(23)01430-1
  14. Olmos, 2024. Treatment patterns and outcomes in metastatic castration-resistant prostate cancer patients with and without somatic or germline alterations in homologous recombination repair genes. https://www.doi.org/10.1016/j.annonc.2024.01.011
  15. de Bono, 2020. Olaparib for metastatic castration-resistant prostate cancer. https://www.doi.org/10.1056/nejmoa1911440
  16. Fan, 2024. Homologous recombination repair gene mutations in prostate cancer: Prevalence and clinical value. https://www.doi.org/10.1007/s12325-024-02844-7
  17. Zhu, 2023. Prognostic value of genomic mutations in metastatic prostate cancer. https://www.doi.org/10.1016/j.heliyon.2023.e13827

Testing for homologous recombination repair mutations (HRRm) in prostate cancer is increasingly important for guiding management and treatment decisions.1

There is a need for clear guidance on HRR testing in prostate cancer

There is general agreement between the available guidelines and consensus statements that all men with metastatic prostate cancer (mPC) should have somatic (tumor) testing for HRR and mismatch repair (MMR) gene mutations, as illustrated in Figure 1. But other recommendations on whom, when and what to test are not yet fully aligned, some guidelines are out of date, and others are yet to include HRR testing at all: clear and consistent recommendations for genetic profiling represent a current unmet need in metastatic castration-resistant prostate cancer (mCRPC).

Chart comparing similarities and differences in HRR testing recommendations in four current guidelines. There is agreement on somatic (tumor) testing in mCRPC and more variation in recommendations for germline testing.

Figure 1. Brief overview of HRR testing recommendations from selected current guidelines.2-5 AUA, American Urological Association; DDR, DNA damage response; EAU, European Association of Urology; ESMO, European Society for Medical Oncology; mCRPC, metastatic castration-resistant prostate cancer; mCSPC, metastatic castration-sensitive prostate cancer; MMR, mismatch repair; mPC, metastatic prostate cancer; NCCN, National Comprehensive Cancer Network; SUO, Society of Urologic Oncology.

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References

  1. Tuffaha, 2024. Guidelines for genetic testing in prostate cancer: A scoping review. https://www.doi.org/10.1038/s41391-023-00676-0
  2. Lowrance, 2023. Updates to advanced prostate cancer: AUA/SUO guideline (2023). https://www.doi.org/10.1097/ju.0000000000003452
  3. Cornford, 2024. EAU-EANM-ESTRO-ESUR-ISUP-SIOG guidelines on prostate cancer-2024 update. Part I: Screening, diagnosis, and local treatment with curative intent. https://www.doi.org/10.1016/j.eururo.2024.03.027
  4. Parker, 2020. Prostate cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. https://www.doi.org/10.1016/j.annonc.2020.06.011
  5. NCCN, 2024. Prostate Cancer. Version 4.2024. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459

Despite testing for homologous recombination repair mutations (HRRm) being recommended by guidelines, access to testing remains uneven, with some groups underserved.1 In a clinical trial of patients with metastatic castration-sensitive prostate cancer (mCSPC), Black patients had similar survival outcomes to White patients2 – yet in the USA, they are twice as likely to die of PC.2,3 Patients with mPC who are Black, Hispanic, Latino, or have low socioeconomic status are significantly less likely to have next-generation sequencing (NGS) testing compared with White patients.1

Inconsistencies in attitudes and access to HRR testing leave some patient groups underserved

Two recent surveys evaluated real-world testing patterns and identified more barriers to equitable testing.4,5

Castro et al. (2023) surveyed 222 physicians who provided information for 1,816 patients with metastatic castration-resistant PC (mCRPC) in the EU5 countries (France, Germany, Italy, Spain, UK).4

  • 670 patients (37%) were tested for HRRm
  • 71% of the 670 tested patients were tested only for BRCA1/2, and the remaining 29% for BRCA1/2 plus other HRR genes
  • Testing rates ranged from 12% in the UK to 49% in Germany

Leith et al. (2022) looked at HRRm testing patterns for 391 physicians and 1,913 patients in the EU5, the USA, and Japan.5

  • The proportion of physicians who tested ranged from 72.2% in the USA to 26.2% in Japan
  • Within the EU5, Germany had the most testers (80.0%) and the UK had the fewest (35.1%)
  • 90.3% of physicians in the USA and 94.0% in Germany had access to testing, versus 56.6% in Japan and 48.6% in the UK

In both surveys, the most common reason for not testing was high cost. This was followed by problems accessing the latest tests, lack of reimbursement, lack of physician awareness of testing, time taken to get results, and testing not being recommended in local guidelines. Other important reasons included no facility for in-house testing, not being comfortable in interpreting results, and lack of adequate sample.4,5

In both surveys, the patients most likely to receive testing had a known family history of PC or breast, ovarian, or pancreatic cancer. Others had an initial diagnosis of locally advanced disease, failure to respond to hormone therapy or chemotherapy, high-risk disease, surgery to treat their PC, or young age at diagnosis.4,5 Conversely, Castro et al. reported that patients were less likely to be tested if they were over 70 years old at the time of data collection.

Finally, poly (ADP-ribose) polymerase inhibitors (PARPi) were approved during data collection by Leith et al., so they asked about the impact of availability on the physicians’ testing decisions. Just over half of physicians in the USA and Japan, and 80% of those in the EU5, said they would be more likely to test for HRRm if a PARPi was available.5

Testing rates in the USA did increase after PARPi approval, from 15% in the first 5 months of 2020 to 62% in the 14 months to the end of 2021.6 However, a third of HRRm-positive patients still did not receive PARPi.6 This lack of comprehensive testing and treatment highlights a major unmet need.

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References

  1. Hage Chehade, 2024. Trends and disparities in next-generation sequencing in metastatic prostate and urothelial cancers. https://www.doi.org/10.1001/jamanetworkopen.2024.23186
  2. Sayegh, 2023. Race and treatment outcomes in patients with metastatic castration-sensitive prostate cancer: A secondary analysis of the SWOG 1216 phase 3 trial. https://www.doi.org/10.1001/jamanetworkopen.2023.26546
  3. Lowder, 2022. Racial disparities in prostate cancer: A complex interplay between socioeconomic inequities and genomics. https://www.doi.org/10.1016/j.canlet.2022.01.028
  4. Castro, 2023. P135 - Homologous recombination repair mutation (HRRm) testing patterns among men with metastatic castration-resistant prostate cancer (mCRPC): Interim results from a real-world (rw) study in Europe. https://www.doi.org/https://doi.org/10.1016/S2666-1683(23)01430-1
  5. Leith, 2022. Real-world homologous recombination repair mutation testing in metastatic castration-resistant prostate cancer in the USA, Europe and Japan. https://www.doi.org/10.2217/fon-2021-1113
  6. Shore, 2024. Homologous recombination repair gene mutation (HRRm) testing patterns and treatment selection from a real-world cohort of patients with metastatic castration-resistant prostate cancer (mCRPC). https://www.doi.org/10.1200/JCO.2024.42.4_suppl.210  

Good-quality samples are key to obtaining usable HRR test results

The first step for targeted therapy is to identify the appropriate gene alterations. Next-generation sequencing (NGS) can identify multiple genes per sample, subject to high-quality tumor tissue samples.1 Tumor testing fails up to 40% of the time,1,2 most often due to inadequate specimen (less than 20% tumor content or insufficient tumor nuclei; tissue volume less than 0.2 mm3) or insufficient DNA yield or quality (age of sample or other DNA degradation problem).1,3 In the PROfound study, 58% of samples produced results for 69% of patients. Most samples were from archival primary prostate tissue. Evaluation of sample characteristics showed that better results were obtained from those that:1

  • Were newly obtained, rather than archival (gradual decline in success with increasing sample age)
  • Had total tissue volume ≥0.6 mm3; radical prostatectomy and transurethral resection of the prostate (TURP) produced more results than prostate core needle biopsy (CNB)
  • Had increased total tumor content (for increased DNA yield), preferably from metastatic lymph node tissue rather than primary tissue or bone samples

Overall, DNA yield was higher with newer, non-prostate tissue compared with archival and primary samples.1 The authors recommended standard formalin fixation of newly collected samples, and not using decalcification on bone samples.1

Aside from variable sample quality, additional limitations of tumor testing are the challenges of biopsy in less accessible metastases, intra-patient and tumor heterogeneity that may result in missed/incorrectly classified cancer, and the impracticality of repeat biopsies to monitor tumor evolution and treatment responses.4 An alternative option is liquid biopsy (LB) for circulating tumor DNA (ctDNA), which can be used to test for germline and somatic alterations.2

Studies comparing tumor tissue biopsy and LB found that ctDNA was evaluable in 92–100% of patients, versus 68–88% of tumor tissue samples.5,6 Mandel et al. (2024) found that LB identified more patients with BRCA1/2 mutations.6 However, there were false negatives with each test type, showing that using a combined testing strategy would give the highest chance of identifying homologous recombination repair (HRR) alterations.5,6 A comparison of the two methods is shown in Figure 1.

List comparing solid versus liquid biopsy. Solid biopsy has surgical risks, pain, and temporal limitations, while liquid biopsy may fail if circulating tumor DNA levels are low.

Figure 1. Comparison of advantages and disadvantages of solid biopsy and liquid biopsy for prostate cancer diagnosis. A combination of both methods may give best results7,8. ctDNA, circulating tumor DNA.

LB can be useful in cases where NGS on tumor tissue has failed, metastatic tissue collection is not possible, or there is no access to tumor testing.2 LB could be used for repeat biopsy, biopsy at disease progression and for bone metastasis, and could help assess tumor heterogeneity.6 It is less invasive and more easily repeatable than tissue biopsy, allowing continual updates, and is usually cheaper and faster.8 Downsides are that LB may fail to detect early disease with low ctDNA concentration, possibly delaying appropriate treatment, and that differing rates of shedding from tumors may lead to an inaccurate clinical picture of heterogeneity.4,8 Lastly, there is still a need for validated sampling guidelines and protocols for use of LB in management of metastatic castration-resistant prostate cancer.

References

  1. Hussain, 2022. Tumor genomic testing for >4,000 men with metastatic castration-resistant prostate cancer in the phase III trial PROfound (Olaparib). https://www.doi.org/10.1158/1078-0432.CCR-21-3940
  2. Schostak, 2024. Practical guidance on establishing a molecular testing pathway for alterations in homologous recombination repair genes in clinical practice for patients with metastatic prostate cancer. https://www.doi.org/10.1016/j.euo.2023.08.004
  3. Hiemenz, 2022. Real-world comprehensive genomic profiling success rates in tissue and liquid prostate carcinoma specimens. https://www.doi.org/10.1093/oncolo/oyac181
  4. Trujillo, 2022. Blood-based liquid biopsies for prostate cancer: clinical opportunities and challenges. https://www.doi.org/10.1038/s41416-022-01881-9
  5. Armstrong, 2022. 1370P Detection of mutations in homologous recombination repair (HRR) genes in tumour tissue (TT) and circulating tumour DNA (ctDNA) from patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) in the phase III PROpel trial. https://www.doi.org/10.1016/j.annonc.2022.07.1502
  6. Mandel, 2024. Feasibility of next-generation sequencing of liquid biopsy (circulating tumor DNA) samples and tumor tissue from patients with metastatic prostate cancer in a real-world clinical setting in Germany. https://www.doi.org/10.1016/j.euf.2024.02.007
  7. Munteanu, 2020. MiRNA-based inspired approach in diagnosis of prostate cancer. https://www.doi.org/10.3390/medicina56020094
  8. Boukovala, 2024. Liquid biopsy into the clinics: Current evidence and future perspectives. https://www.doi.org/10.1016/j.jlb.2024.100146  

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