APCCC 2021: Somatic Testing – When and What? (Including Mismatch Repair Evaluation)

(UroToday.com) The third and final session of the Advanced Prostate Cancer Consensus Conference 2021 which was hosted virtually in the context of the COVID-19 pandemic focused on molecular characterization of both tissue and blood, with a focus on implications for treatment with PARP inhibitors and beyond. In this context, Dr. Maha Hussain discussed the role of somatic tumor testing.

She began by highlight that, while we are just entering era of personalized medicine, we have been testing targeted therapy for a long time in prostate cancer including agents targeting angiogenesis, androgen signalling, apoptosis, the cell cycle, DNA repair pathways, the bone microenvironment, immune modulation, and others. Most of these were tested without the use of biomarker selection, however. She then emphasized that, according to the NCI, personalized medicine depends on the use of information about a person’s genes or proteins to prevent, diagnose, or treat disease. The era of personalized medicine in prostate cancer began in 2017 with the approval of pembrolizumab in a tumor-agnostic manner for patients with microsatellite-instability high or mismatch repair-deficient tumors. This represents about 3% of patients with metastatic castration resistant prostate cancer (mCRPC). Precision medicine in prostate cancer took a large leap forward in May 2020 with the approval of the PARP inhibitors olaparib and rucaparib for patients with mCRPC with deleterious mutations in the DNA repair pathway. Rucaparib is approved for men with BRCA mutations and mCRPC who have previously received at least one androgen axis targeting agent and taxane-based chemotherapy while olaparib is approved for men with deleterious mutations in 14 different homologous recombination repair genes who have mCRPC and have progressed following treatment with enzalutamide or apalutamide.

As the relevant ASCO guidelines are not finalized, she relied on NCCN guidelines to guide the question of how and who to undertake genetic analysis. In terms of somatic tumor testing, the NCCN guidelines recommend appropriate pre-test counseling to consider their role in treatment decision making, eligibility for biomarker-directed therapy, genetic counseling, early use of platinum therapy, and eligibility for trials. Further, the guidelines highlight that profiles may change as a result of treatment so re-evaluation may be required. In terms of how to conduct testing, the guideline focuses heavily on DDR genes (including BRCA1, BRCA2, and others) and evidence for MSI-high status or defects in MMR. Further tumor mutational burden testing may be considered in mCRPC.

Again highlighting the NCCN guidelines, she emphasized that somatic testing is recommended for all patients with metastatic disease and should be considered in those with regional disease. Beyond the NCCN guidelines, Dr. Hussain emphasized that the AUA/ASTRO/SUO guidelines from 2020 on Advanced Prostate Cancer recommend offering germline and somatic tumor testing for both DNA repair deficiency and microsatellite instability.

Thinking next about how to accomplish this, Dr. Hussain emphasized that tissue quality declines over time and as a result, testing success decreases. However, even at more than 10 years, almost half of patients (47%) will have successful tumor testing. Further, testing success is somewhat higher when newly collected samples are used (63.9%) compared to archived samples (56.9%). Similarly, testing success rates are higher for biopsies of metastatic lesions (63.7%) compared to primary tumors (56.3%) though this may be confounded by the time since sample acquisition. Considering tumor sites for testing, she highlighted that soft tissue biopsy is associated higher tumor testing success than bone biopsy.



Leveraging lessons learned from PROfound, she highlighted that the overall tissue collection success rate for next generation sequencing was 69%. This rate was higher among newly collected tissue samples, “younger” archival samples (with a decline in success after 5 years), and biopsy from metastatic sites which may be due to higher cellularity and tumor contents (though confounded by the fact that primary tumor samples are more likely to be archival). Considering pragmatic factors, she emphasized the preference for multiple core need biopsy samples with embedding in one formalin-fixed paraffin-embedded block. For bony biopsies, she further highlighted that it is critical to avoid strong acid decalcification as this degrades sample quality. In the case of newly harvested bone biopsies, she further recommended that decalcification should not be performed.

Presented by: Maha Hussain, MD, FACP, FASCO, is the Genevieve Teuton Professor of Medicine in the Division of Hematology Oncology, Department of Medicine, and the Deputy Director at the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine.

Written by: Christopher J.D. Wallis, University of Toronto, Twitter: @WallisCJD during the 2021 Advanced Prostate Cancer Consensus Conference, Saturday, October 9, 2021.

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APCCC 2021: Summary of Panel Responses Regarding Tumor Molecular Testing