3648-Prostate cancer – panel testing

eviQ cancer genetics consensus statement: scope of genetic testing protocols

Target population

Individual with prostate cancer where a pathogenic variant in a gene listed below has been detected on tumour testing.
Individual with castrate-resistant metastatic prostate cancer (regardless of other personal or family history factors) for whom genetic testing on tumour DNA is not clinically feasible, to determine eligibility for a PARP inhibitor.
Individual with prostate cancer and ≥ 10% probability of detecting a BRCA1 or BRCA2 pathogenic variant using a validated pathogenic variant prediction tool (e.g. CanRisk opens in a new tab or window).
Individual with prostate cancer with intraductal/ductal histology.
Individual with prostate cancer from a population where a founder pathogenic variant of high prevalence exists (e.g. Ashkenazi Jewish, Swedish/Nordic).

Recommendations for individuals for whom germline and/or tumour testing may be indicated to inform systemic therapy options can be found here:

Note

In the following settings a variant-specific test (rather than sequencing a single gene or gene panel) may be more appropriate and cost effective:

Where a known germline pathogenic variant has been identified in a relative.
Where a specific pathogenic variant has been identified on somatic tumour testing.

Genetic testing is important for good clinical care of individuals who are suspected of having a familial cancer/tumour predisposition.

Investigations before panel testing

The results of the following investigations may significantly influence the likelihood of detecting a heritable pathogenic variant:

results of tumour sequencing for genes included in the panel.

Probability of a heritable pathogenic variant

Factor	Gene	Probability of detecting a heritable pathogenic variant
Metastatic prostate cancer	Panel^* BRCA2/PALB2/ATM	11.8-15.4%^r ^r 5.1%^r
Metastatic prostate cancer and family history that meets criteria for HBOC or Lynch syndrome**	Panel^*	10.5-15.9%^r ^r
Ductal/intraductal histology	Panel^*	20-40%^r ^r
Swedish/Nordic ancestry and prostate cancer diagnosed ≤ 55 years	HOXB13	10.3%^r

Abbreviation: HBOC - hereditary breast or ovarian cancer
* Genes included in the panel varied in each study. The clinical significance with respect to prostate cancer risk is unknown for many of the genes included in these panels and this should be considered when deciding which genes to order
** Criteria used were: family history of non-prostate cancer,^r modified Bethesda criteria^r for Lynch syndrome, and NCCN guidelines “Genetic/familial high-risk assessment: breast and ovarian cancer” version 1.2017^r for HBOC

Genes that might be included in a prostate cancer panel

When choosing genes to include in a gene panel, care should be taken to select genes which have both clinical validity and clinical utility for the phenotype of concern.

The likelihood of identifying a variant of uncertain significance increases as the number of genes included in a panel increases.

Genes associated with prostate cancer
Gene^	Comments
ATM	Prostate cancer risk increased but not well quantified An eviQ risk management protocol has been developed for non-prostate related cancers^^
BRCA1	Prostate cancer risk may be increased but not well quantified An eviQ risk management protocol has been developed Potential treatment implications for affected individuals^^^
BRCA2	Increased risk of prostate cancer, associated with earlier onset, higher grade, higher stage and worse prognosis An eviQ risk management protocol has been developed Potential treatment implications for affected individuals^^^
HOXB13 G84E (c.251G>A)	Increased risk of prostate cancer^# An eviQ risk management protocol has been developed
PALB2	Prostate cancer risk may be increased but not well quantified An eviQ risk management protocol has been developed for non-prostate related cancers^^

^ Genes are listed alphabetically; the order of listing does not give any indication of the clinical validity/utility of testing the gene.
^^ Gene-specific risk management guidelines for prostate cancer have not been developed by eviQ due to insufficient evidence.
^^^ Potential treatment implications will vary between patients and need to be discussed with the treating specialist.
^#From one publication^r, based on early data from a founder population and may be an overestimation of risk.

Circumstances in which testing is not indicated

Predictive testing should never be ordered for a variant of uncertain significance or a benign/likely benign variant.

Testing methods

In addition to sequencing using genomic sequencing (“next generation sequencing” or NGS), a range of other testing methodologies may be needed to identify pathogenic changes in the genes in the panel including

Sanger sequencing
long range PCR
copy number analysis (e.g. MLPA)
analysis for structural rearrangements

Information about DNA tests and testing laboratories is available from:

A variant-specific test (rather than sequencing a single gene or gene panel) may be more appropriate and cost effective where a relative is known to have a germline pathogenic variant or a pathogenic variant has been identified in the patient’s tumour.

If these genes are tested using genomic sequencing (“next generation sequencing” or NGS), and testing has not identified a pathogenic variant, the value of testing using another methodology should be considered.

If genetic testing in DNA from peripheral blood does not identify a pathogenic variant, testing of other tumour and tissue samples may be indicated to assess for mosaicism.

Result interpretation

Result	Reference databases	Considerations and advice
Pathogenic variant search
Pathogenic variant	National Human Genome Research Institute opens in a new tab or window LOVD opens in a new tab or window InSiGHT opens in a new tab or window	ATM (monoallelic pathogenic variants) – risk management BRCA1 or BRCA2 – risk management (male) HOXB13 (G84E) – risk management PALB2 – risk management
Variant of uncertain significance		Review pathogenicity of variants periodically Identify other genes for which a pathogenic variant search could be considered
No reportable variant		Identify other genes for which a pathogenic variant search could be considered

If a pathogenic variant is identified, refer to a clinical genetics service or familial cancer centre opens in a new tab or window for review, family risk notification and predictive testing.

If a variant of uncertain significance is identified, consider referral to a clinical genetics service or familial cancer centre for review and guidance.

If a mosaic pathogenic variant is identified, refer to a clinical genetics service or familial cancer centre for review and guidance about the penetrance of phenotypic features (including cancer/tumour risk).

For additional information about the management of genetic test results when ordered by a non-genetic healthcare professional refer to eviQ’s Guide for health professionals ordering genetic testing.

Website resources

Centre for Genetics Education - NSW Health opens in a new tab or window

The GeneEQUAL Toolkit - Supporting Inclusive, Person-Centred and Respectful Genetic Health Care opens in a new tab or window

CanRisk opens in a new tab or window

References References

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[%abstract%]
: Giri, V.N., S.E. Hegarty, C. Hyatt, et al. 2019. "Germline genetic testing for inherited prostate cancer in practice: Implications for genetic testing, precision therapy, and cascade testing." Prostate 79(4):333-339.

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BACKGROUND: Genetic testing capability and guidelines are rapidly expanding to assess inherited prostate cancer (PCA). Clinical genetic data from multigene testing can provide insights into the germline pathogenic variant (PV) spectrum and correlates in men with PCA unselected for metastatic disease to optimize identification of men for genetic evaluation and management. METHODS: A retrospective cross-sectional analysis was conducted of de-identified clinical genetic testing data from a large commercial genetic testing laboratory in the US. ICD-10 claims codes were used to identify men with PCA, along with family history data. Gleason score was abstracted from test request forms. Overall PV rate among men with PCA was estimated, along with PVs in DNA repair genes. Family history and Gleason score association to germline DNA repair PVs was assessed using Fisher's exact test with correction for false-discovery. RESULTS: As of August 2017, genetic results were available on 1328 men with PCA. Overall PV rate was 15.6%, with 10.9% of PV in DNA repair genes. PVs were most commonly identified in BRCA2 (4.5%), CHEK2 (2.2%), ATM (1.8%), and BRCA1 (1.1%). Breast cancer family history was significantly associated with germline DNA repair PVs (OR 1.89, [95%CI 1.33, 2.68], P = 0.003). Among men with Gleason score>= 6 (n = 706), Gleason> = 8 was significantly associated with DNA repair PVs (OR 1.85 [95%CI 1.22, 2.80], P = 0.004). CONCLUSIONS: A substantial proportion of men with PCA unselected for metastatic disease carry germline DNA repair PVs. Breast cancer family history and high Gleason score are important predictors to identify men with PCA who may carry germline DNA repair PVs. Our findings support current NCCN guidelines and have implications for genetic assessment, therapeutic management, and cascade testing for men with PCA and their families.
: Giri, V.N., K.E. Knudsen, W.K. Kelly, et al. 2018. "Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017." Journal of Clinical Oncology 36(4):414-424.

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Purpose: Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management.MethodsAn expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review.

Results: Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy.

Conclusion:To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA—a clinically heterogeneous disease.
: Karlsson, Q., M. N. Brook, T. Dadaev, et al. 2021. "Rare germline variants in ATM predispose to prostate cancer: A PRACTICAL consortium study." Eur Urol Oncol 4(4): 570-579.

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BACKGROUND: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes. OBJECTIVE: To precisely estimate the contribution of germline ATM mutations to PrCa risk. DESIGN, SETTING, AND PARTICIPANTS: We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated. RESULTS AND LIMITATIONS: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (pdifference = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7). CONCLUSIONS: Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families. PATIENT SUMMARY: In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.
: Lecarpentier, J., V. Silvestri, K. B. Kuchenbaecker, et al. 2017. "Prediction of breast and prostate cancer risks in male BRCA1 and BRCA2 mutation carriers using polygenic risk scores." J Clin Oncol 35(20):2240-2250.

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Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 x 10(-6)). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 x 10(-9)). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.
: Nyberg, T., D. Frost, D. Barrowdale, et al. 2020. "Prostate Cancer Risks for Male BRCA1 and BRCA2 Mutation Carriers: A Prospective Cohort Study." Eur Urol 77(1): 24-35.

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BACKGROUND: BRCA1 and BRCA2 mutations have been associated with prostate cancer (PCa) risk but a wide range of risk estimates have been reported that are based on retrospective studies. OBJECTIVE: To estimate relative and absolute PCa risks associated with BRCA1/2 mutations and to assess risk modification by age, family history, and mutation location. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort study of male BRCA1 (n = 376) and BRCA2 carriers (n = 447) identified in clinical genetics centres in the UK and Ireland (median follow-up 5.9 and 5.3yr, respectively). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Standardised incidence/mortality ratios (SIRs/SMRs) relative to population incidences or mortality rates, absolute risks, and hazard ratios (HRs) were estimated using cohort and survival analysis methods. RESULTS AND LIMITATIONS: Sixteen BRCA1 and 26 BRCA2 carriers were diagnosed with PCa during follow-up. BRCA2 carriers had an SIR of 4.45 (95% confidence interval [CI] 2.99-6.61) and absolute PCa risk of 27% (95% CI 17-41%) and 60% (95% CI 43-78%) by ages 75 and 85yr, respectively. For BRCA1 carriers, the overall SIR was 2.35 (95% CI 1.43-3.88); the corresponding SIR at age <65yr was 3.57 (95% CI 1.68-7.58). However, the BRCA1 SIR varied between 0.74 and 2.83 in sensitivity analyses to assess potential screening effects. PCa risk for BRCA2 carriers increased with family history (HR per affected relative 1.68, 95% CI 0.99-2.85). BRCA2 mutations in the region bounded by positions c.2831 and c.6401 were associated with an SIR of 2.46 (95% CI 1.07-5.64) compared to population incidences, corresponding to lower PCa risk (HR 0.37, 95% CI 0.14-0.96) than for mutations outside the region. BRCA2 carriers had a stronger association with Gleason score >/=7 (SIR 5.07, 95% CI 3.20-8.02) than Gleason score </=6 PCa (SIR 3.03, 95% CI 1.24-7.44), and a higher risk of death from PCa (SMR 3.85, 95% CI 1.44-10.3). Limitations include potential screening effects for these known mutation carriers; however, the BRCA2 results were robust to multiple sensitivity analyses. CONCLUSIONS: The results substantiate PCa risk patterns indicated by retrospective analyses for BRCA2 carriers, including further evidence of association with aggressive PCa, and give some support for a weaker association in BRCA1 carriers. PATIENT SUMMARY: In this study we followed unaffected men known to carry mutations in the BRCA1 and BRCA2 genes to investigate whether they are at higher risk of developing prostate cancer compared to the general population. We found that carriers of BRCA2 mutations have a high risk of developing prostate cancer, particularly more aggressive prostate cancer, and that this risk varies by family history of prostate cancer and the location of the mutation within the gene.

History

Version 4

Date	Summary of changes
19/04/2023	Protocol reviewed at October 2022 cancer genetics reference committee. Discussion continued via email and MS Teams. Approved for publication with the following changes made: 2023 cancer genetics template changes applied throughout document "Male" changed to "individual" throughout document Target population: criteria reviewed and updated Investigations before panel testing: removed "immunohistochemistry for the MMR proteins MLH1, MSH2, MSH6 and PMS2 if suspicious of Lynch syndrome" and "microsatellite instability (MSI) testing" Probability of a heritable pathogenic variant: added "Ductal/intraductal histology" and removed "Metastatic prostate cancer diagnosed <60 years" and "Prostate cancer and loss of staining of DNA MMR protein by immunohistochemistry" Genes that might be included in a prostate cancer panel: added "PALB2" and removed "DNA mismatch repair genes (MSH2, MSH6, MLH1, PMS2)" Result interpretation: added link to "PALB2 – risk management" and removed link to "MMR genes – risk management" Approved on 19/04/2023, changes published on eviQ on 02/05/2023. Version number increased to V.4. Review in 2 years.
20/08/2024	The following section of the document updated by consensus of the reference committee co-chairs: Target population: 2nd dot point added "...to determine eligibility for a PARP inhibitor."

Date

Summary of changes

19/04/2023

Protocol reviewed at October 2022 cancer genetics reference committee. Discussion continued via email and MS Teams. Approved for publication with the following changes made:

2023 cancer genetics template changes applied throughout document
"Male" changed to "individual" throughout document
Target population: criteria reviewed and updated
Investigations before panel testing: removed "immunohistochemistry for the MMR proteins MLH1, MSH2, MSH6 and PMS2 if suspicious of Lynch syndrome" and "microsatellite instability (MSI) testing"
Probability of a heritable pathogenic variant: added "Ductal/intraductal histology" and removed "Metastatic prostate cancer diagnosed <60 years" and "Prostate cancer and loss of staining of DNA MMR protein by immunohistochemistry"
Genes that might be included in a prostate cancer panel: added "PALB2" and removed "DNA mismatch repair genes (MSH2, MSH6, MLH1, PMS2)"
Result interpretation: added link to "PALB2 – risk management" and removed link to "MMR genes – risk management"

Approved on 19/04/2023, changes published on eviQ on 02/05/2023. Version number increased to V.4. Review in 2 years.

20/08/2024

The following section of the document updated by consensus of the reference committee co-chairs:

Target population: 2nd dot point added "...to determine eligibility for a PARP inhibitor."

Version 3

Date	Summary of changes
06/05/2022	Following updates to the ATM risk management document (ID 1610), the following changes were made to the Prostate cancer – panel testing document: Genes that might be included in a prostate cancer panel: ATM gene added to table. Comments re ATM added to table 'Prostate cancer risk increased but not well quantified' and 'Risk management guidelines available (eviQ) for non-prostate related cancers' HOXB13: comment regarding risk management guidelines available changed from 'consensus' to 'eviQ' Result interpretation table: added links to ATM (monoallelic pathogenic variants) – risk management' and 'HOXB13 (G84E) – risk management (male)' in the Considerations and advice column. Removed link to BRAC1 or BRCA2 – risk management (female). Version increased to V.3.

Date

Summary of changes

06/05/2022

Following updates to the ATM risk management document (ID 1610), the following changes were made to the Prostate cancer – panel testing document:

Genes that might be included in a prostate cancer panel:
- ATM gene added to table. Comments re ATM added to table 'Prostate cancer risk increased but not well quantified' and 'Risk management guidelines available (eviQ) for non-prostate related cancers'
- HOXB13: comment regarding risk management guidelines available changed from 'consensus' to 'eviQ'
Result interpretation table: added links to ATM (monoallelic pathogenic variants) – risk management' and 'HOXB13 (G84E) – risk management (male)' in the Considerations and advice column. Removed link to BRAC1 or BRCA2 – risk management (female).

Version increased to V.3.

Version 2

Date	Summary of changes
09/12/2020	The following sections of the document were updated to align with the new eviQ cancer genetics panel testing template: Related pages: added links to "Guide for health professionals ordering genetic testing" and "Cancer predisposition genes: population carrier frequency". Removed link to "Pre-test counselling" Circumstances in which testing is not indicated: template wording updated Testing methods: template wording updated Result interpretation: table format updated. Template sentence added (including link to "Guide for health professionals ordering genetic testing") Counselling: section deleted Website resources: section deleted Version number increased to V.2.
13/10/2021	Protocol title changed from 'Prostate cancer panel testing' to 'Prostate cancer – panel testing'.
10/11/2021	Removed link to "European Directory of DNA Diagnostic Laboratories"

Date

Summary of changes

09/12/2020

The following sections of the document were updated to align with the new eviQ cancer genetics panel testing template:

Related pages: added links to "Guide for health professionals ordering genetic testing" and "Cancer predisposition genes: population carrier frequency". Removed link to "Pre-test counselling"
Circumstances in which testing is not indicated: template wording updated
Testing methods: template wording updated
Result interpretation: table format updated. Template sentence added (including link to "Guide for health professionals ordering genetic testing")
Counselling: section deleted
Website resources: section deleted
Version number increased to V.2.

13/10/2021

Protocol title changed from 'Prostate cancer panel testing' to 'Prostate cancer – panel testing'.

10/11/2021

Removed link to "European Directory of DNA Diagnostic Laboratories"

Version 1

Date	Summary of changes
12/08/2020	New protocol developed and discussed at May 2019 and October 2019 cancer genetics reference committee meetings. Discussions continued via email. Approved for publication as V.1. Review in 2 years.

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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First approved:: 12 August 2020
Last reviewed:: 19 April 2023
Review due:: 30 June 2025

The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/3648

17 May 2025

Prostate cancer – panel testing

Note

References References

Bibliography

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