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Profiling of circulating tumor (ct)-DNA for potentially actionable targets in prostate cancer (PCa).
Background: Genomic profiling of metastatic PCa tissue is challenging and circulating tumor cells may not recapitulate entire tumor biology. Cell-free ctDNA is detectable in most patients (pts) with advanced cancer and may capture relevant alterations in cancer cells from different tumor sites. We studied the frequency of ctDNA alterations in potentially actionable genes in pts with PCa. Methods: Patients with PCa that underwent ctDNA analysis using Guardant360 were identified. A 70-gene ctDNA next generation sequencing panel from a CLIA-licensed, CAP-accredited laboratory (Guardant Health, Inc.) was used to sequence all exons in 29 cancer genes, critical exons in 39 genes, and amplifications (16 genes), fusions (6 genes), indels (3 genes), harvested from 10 mL of peripheral blood. Results: We studied 449 pts with PCa (median age 71, range 42-92) with at least one ctDNA test. ctDNA alterations were detectable in 386 patients (84%). Genes with the highest frequency of somatic alteration including amplification (*) in the overall group were: TP53 (54%), AR* (47%), FGFR1/2/3* (20%), MYC* (19%), PIK3CA* (19%), CDK4/6* (16%), EGFR (15%), BRAF*(14%), APC (13%), NF1 and MET (each 12%). A subset of 128 pts with confirmed metastatic castration-resistant prostate cancer (mCRPC) had a similar distribution and frequency of genomic alterations compared to the overall group. Recurrent somatic mutations in AR, PIK3CA, APC and CTNNB1 were identified in the mCRPC cohort at similar frequencies compared to prior studies of tumor tissue analyses. 38 mCPRC pts were confirmed to receive ≥ 4 cycles of 1st or 2nd line taxane chemotherapy and had f/u data; TP53 mutations were associated with longer PFS (PCWG2 criteria; p = 0.032) and PIK3CA mutations were associated with shorter PFS (p = 0.024) following taxane therapy, using a log rank test. Serial ctDNA profiling available in 10 pts revealed clonal evolution of alterations in AR, PIK3CA,BRCA2 and NF1. Conclusions: In this large dataset, ctDNA was frequently detected in pts with PCa with an alteration profile similar to that seen in tumor tissue. ctDNA analysis offers a non-invasive means of serially profiling tumor DNA to identify treatment targets and emerging markers of resistance.
Abstracts by Guru Sonpavde:
AR nuclear localization and microtubule bundling as markers of docetaxel and cabazitaxel sensitivity in metastatic castration-resistant prostate cancer (mCRPC): Prospective biomarker analysis from TAXYNERGY.Meeting: 2017 Genitourinary Cancers Symposium | Abstract No: 134
Circulating tumor (ct)-DNA alterations in advanced urothelial carcinoma: Association with outcomes and evolution with therapy.Meeting: 2017 Genitourinary Cancers Symposium | Abstract No: 334
Circulating tumor (ct)-DNA alterations in metastatic castration-resistant prostate cancer (mCRPC): Association with outcomes and evolution with therapy.Meeting: 2017 Genitourinary Cancers Symposium | Abstract No: 149