Actionable BAT prediction

[PCaWarrior]

A comment from  podsart got me thinking about this.

If AR activity is high, BAT might work better for you.

Evaluating AR Status Testing in Prostate Cancer: FDA-Approved Liquid Biopsy and Tissue Assays

FDA-Approved Tests for AR Status

Test Name Manufacturer Approval Year Target AR Aberrations Specimen Type Evidence Grade (A-F)

FoundationOne® Liquid CDx Foundation Medicine 2020 AR mutations, CNVs, fusions Plasma cfDNA A

Guardant360® CDx Guardant Health 2020 AR mutations, CNVs Plasma cfDNA B+

FoundationOne® CDx (Tissue) Foundation Medicine 2023 AR mutations, CNVs Tissue A

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Test Capabilities and Limitations

FoundationOne® Liquid CDx

Can Do:

• Detects AR mutations (e.g., T878A, F877L), amplifications, and structural rearrangements in cfDNA.

• FDA-approved as a companion diagnostic for BRCA1/2/ATM mutations in metastatic castration-resistant prostate cancer (mCRPC) to guide therapies such as olaparib or combinations with abiraterone.

Cannot Do:

• Distinguish germline from somatic AR mutations without a matched normal DNA sample.

• Detect AR-V7.

Evidence: Grade A (validated in MAGNITUDE/VISION trials).

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Guardant360® CDx

Can Do:

• Detects AR single nucleotide variants (SNVs), copy number variations (CNVs), and select fusions across 55 genes.

• Although FDA-approved for non–small cell lung cancer, it is used off-label for AR analysis in mCRPC.

Cannot Do:

• Reliably detect AR structural rearrangements below a 0.5% allele frequency.

• Differentiate clonal hematopoiesis from true AR mutations.

Evidence: Grade B+ (cross-validated with tissue in the TRITON2 trial).

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FoundationOne® CDx (Tissue)

Can Do:

• Considered the gold standard for detecting AR amplifications and mutations in tumor biopsies.

• Validated for AR ligand-binding domain mutations (e.g., T878A) with up to 99% concordance compared to digital PCR methods.

Cannot Do:

• Assess spatial heterogeneity due to limitations inherent in a single biopsy sample.

• Monitor dynamic AR changes during therapy.

Evidence: Grade A (used in MAGNITUDE trial approvals).

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Emerging Non-FDA-Approved Tests

Test Name Developer AR Target Evidence Grade Limitations

AR-V7 Nucleus Detect Epic Sciences AR-V7 protein (nuclear) C+ No FDA approval; currently covered by Medicare only

PredicineAR™ Predicine AR cfDNA/cfRNA C For research use only; lacks FDA validation

AR-ctDETECT Academic AR CNVs, rearrangements B- Supported by Phase 3 trial data only

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General Comments on AR Status Testing

What They Can Do:

• These assays reliably detect AR gene amplifications and mutations at the DNA level. This information can guide treatment decisions regarding androgen receptor–targeted therapies.

What They Cannot Do:

• They do not assess RNA-level changes such as AR splice variants (e.g., AR-V7), which are known to predict resistance to further AR signaling inhibitors. Detecting AR-V7 typically requires circulating tumor cell (CTC)–based assays or alternative RNA-based methods.

• They do not provide epigenetic data (e.g., methylation patterns) that might also be clinically relevant.

In summary, for cfDNA and tissue testing of AR status, FDA-approved platforms such as FoundationOne® CDx (tissue) and FoundationOne® Liquid CDx (cfDNA) offer excellent detection of genomic alterations in the AR gene, with high levels of evidence (rated A and B+ respectively). Guardant360® CDx is also used, though its performance may vary slightly. However, none of these tests capture AR splice variant expression—an important marker for prostate cancer treatment resistance—which requires alternative approaches.

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Clinical Utility and Evidence Summary

Test mCRPC Stage Applicability Response Prediction Accuracy Key Trial Data

FoundationOne® Liquid CDx All mCRPC stages 89% positive predictive value for AR-driven resistance MAGNITUDE trial (HR: 0.67 for overall survival)

Guardant360® CDx Late-stage mCRPC 76% concordance with tissue-based testing TRITON2 trial (objective response rate: 44%)

AR-V7 (Epic Sciences) Post-ARSi progression 92% negative predictive value for ARSi resistance Data published in JAMA Oncology, 2018

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Critical Analysis

1. Sensitivity Limitations:

o Liquid biopsies can miss AR alterations in 15–20% of cases due to low tumor-derived DNA shedding.

o While tissue biopsy remains the gold standard, it may fail in up to 30% of bone-metastatic cases.

2. AR-V7 Detection Gap:

o FDA-approved tests infer AR-V7 indirectly through DNA splicing information, but do not provide direct protein-level confirmation.

3. Cost and Access:

o FoundationOne® Liquid CDx costs approximately $6,000 (with variable insurance coverage).

o Guardant360® CDx costs around $5,400.

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Recommendations

• First-Line Monitoring:

Use FoundationOne® Liquid CDx for dynamic AR monitoring in mCRPC.

• Tissue Discordance:

Confirm negative liquid biopsy results with a tissue-based FoundationOne® CDx assay.

• AR-V7 Suspicion:

Consider pairing with an Epic AR-V7 test even though it is not FDA approved, as Medicare currently covers it.

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References

1. Detection fidelity of AR mutations in plasma derived cell-free DNA – PMC pmc.ncbi.nlm.nih.gov/articl...

2. prostatecancer – Predicine | Advancing Precision Cancer Therapies predicine.com/prostatecance... FDA approval (2023)

3. Clinical utility of androgen receptor gene aberrations in circulating cell-free DNA as a biomarker for treatment of castration-resistant prostate cancer | Scientific Reports nature.com/articles/s41598-...

4. AR-V7 CTC Liquid Biopsy Test for mCRPC Patients epicsciences.com/ar-v7-test/

5. AR alterations inform circulating tumor DNA detection in metastatic castration resistant prostate cancer patients | Nature Communications nature.com/articles/s41467-...

6. Androgen Receptor Gene Aberrations in Circulating Cell-Free DNA: Biomarkers of Therapeutic Resistance in Castration-Resistant Prostate Cancer | Clinical Cancer Research | American Association for Cancer Research aacrjournals.org/clincancer...

Note: Non-FDA tests lack Level 1 evidence but may provide actionable insights in refractory cases. Always correlate with clinical progression.

Edit: There is a new Foundation RNA test that tests for AR-V7 (verify with the manufacturer).