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Clinical utility of FoundationOne tissue molecular profiling in men with metastatic prostate cancer.

ABSTRACT: PURPOSE:Targeted inhibitors and immunotherapy have entered the treatment landscape of metastatic prostate cancer. Genomic testing may uncover which patients benefit most from these therapies. We report the clinical utility and benefits of FoundationOne testing in men with advanced prostate cancer. PATIENTS AND METHODS:We retrospectively identified all men with prostate cancer who received tissue FoundationOne testing at our institution between January 2010 and April 2017. Genomic alterations, treatment selection based on FoundationOne results, and clinical outcomes including response and duration of therapy following matched targeted therapy were analyzed. RESULTS:A total of 77 men with metastatic prostate cancer were referred for FoundationOne testing; 59 (77%) had sufficient tumor tissue for testing. Of these, 22% (17/77) of men had a targetable mutation and 9% (7/77) of men received matched off-label targeted therapy. Overall, 5% (4/77) of patients derived clinical benefit. One patient with a BRCA2 loss had a complete response on olaparib (>27 months) and 3 patients (ATM substitution, PALB2 frameshift, CDK12 frameshift) had stable disease with olaparib (10.3, 18.7, and 7.8 months, respectively). Three patients (BRCA2 frameshift, PDL1?+?PDL2 amplification, PMS2 missense) had progressive disease despite targeted therapy. CONCLUSIONS:Tissue genomic testing can uncover patients who may benefit from targeted therapies such as poly(adenosine diphosphate-ribose) polymerase inhibitors or immunotherapy. In our limited single institution study, genomic testing led to clinical benefit in 5% of patients. Combined germline and circulating tumor DNA testing may be helpful to identify additional patients suitable for matched genomic therapies.

SUBMITTER: Zhu J

PROVIDER: S-EPMC6823135 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Clinical utility of FoundationOne tissue molecular profiling in men with metastatic prostate cancer.

Zhu Jason J Tucker Matthew M Marin Daniele D Gupta Rajan T RT Healy Patrick P Humeniuk Michael M Jarvis Casey C Zhang Tian T McNamara Megan M George Daniel J DJ Wu Yuan Y Lisi Stacey S Armstrong Andrew J AJ

Urologic oncology 20190719 11

<h4>Purpose</h4>Targeted inhibitors and immunotherapy have entered the treatment landscape of metastatic prostate cancer. Genomic testing may uncover which patients benefit most from these therapies. We report the clinical utility and benefits of FoundationOne testing in men with advanced prostate cancer.<h4>Patients and methods</h4>We retrospectively identified all men with prostate cancer who received tissue FoundationOne testing at our institution between January 2010 and April 2017. Genomic ...[more]

PMID: 31327751

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Project description:BackgroundComprehensive molecular profiling led to the recognition of multiple prostate cancer (PCa) molecular subtypes and driving alterations, but translating these findings to clinical practice is challenging.Patients and methodsWe developed a formalin-fixed paraffin-embedded (FFPE) tissue compatible integrative assay for PCa molecular subtyping and interrogation of relevant genetic/transcriptomic alterations (MiPC). We applied MiPC, which combines capture-based next generation sequencing and quantitative reverse transcription PCR (qRT-PCR), to 53 FFPE PCa specimens representing cases not well represented in frozen tissue cohorts, including 8 paired primary tumor and lymph node metastases. Results were validated using multiplexed PCR based NGS and Sanger sequencing.ResultsWe identified known and novel potential driving, somatic mutations and copy number alterations, including a novel BRAF T599_V600insHT mutation and CYP11B2 amplification in a patient treated with ketoconazole (a potent CYP11B2 inhibitor). qRT-PCR integration enabled comprehensive molecular subtyping and provided complementary information, such as androgen receptor (AR) target gene module assessment in advanced cases and SPINK1 over-expression. MiPC identified highly concordant profiles for all 8 tumor/lymph node metastasis pairs, consistent with limited heterogeneity amongst driving events. MiPC and exome sequencing were performed on separately isolated conventional acinar PCa and prostatic small cell carcinoma (SCC) components from the same FFPE resection specimen to enable direct comparison of histologically distinct components. While both components showed TMPRSS2:ERG fusions, the SCC component exclusively harbored complete TP53 inactivation (frameshift variant and copy loss) and two CREBBP mutations.ConclusionsOur results demonstrate the feasibility of integrative profiling of routine PCa specimens, which may have utility for understanding disease biology and enabling personalized medicine applications.

Project description:BackgroundThe androgen receptor (AR) remains a critical driver in metastatic castration-resistant prostate cancer (mCRPC). Profiling AR aberrations in both circulating DNA and RNA may identify key predictive and/or prognostic biomarkers in the context of contemporary systemic therapy.ObjectiveTo profile AR aberrations in circulating nucleic acids and correlate with clinical outcomes.Design, setting, and participantsWe prospectively enrolled 67 mCRPC patients commencing AR pathway inhibitors (ARPIs; n = 41) or taxane chemotherapy (n = 26). Using a first-in-class next-generation sequencing-based assay, we performed integrated cell-free DNA (cfDNA) and cell-free RNA (cfRNA) profiling from a single 10 ml blood tube.Outcome measurements and statistical analysisKaplan-Meier survival estimates and multivariable Cox regression analyses were used to assess associations between clinical outcomes and the following AR aberrations: copy number variation, splice variants (AR-V7 and AR-V9) and somatic mutations.Results and limitationsCell-free DNA and cfRNA were successfully sequenced in 67 (100%) and 59 (88%) patients, respectively. Thirty-six (54%) patients had one or more AR aberrations. AR gain and cumulative number of AR aberrations were independently associated with clinical/radiographic progression-free survival (PFS; hazard ratio [HR] 3.2, p = 0.01 and HR 3.0 for 0 vs ≥2, p = 0.04) and overall survival (HR 2.8, p = 0.04 and HR 2.9 for 0 vs ≥2, p = 0.03). Notably, concurrent AR gain and AR splice variant expression (AR gain/AR-V+) was associated with shorter prostate-specific antigen PFS on both ARPIs (HR 6.7, p = 0.009) and chemotherapy (HR 3.9, p = 0.04). Importantly, key findings were validated in an independent cohort of mCRPC patients (n = 40), including shorter OS in AR gain/AR-V+ disease (HR 3.3, p = 0.02). Limitations include sample size and follow-up period.ConclusionsWe demonstrate the utility of a novel, multianalyte liquid biopsy assay capable of simultaneously detecting AR alterations in cfDNA and cfRNA. Concurrent profiling of cfDNA and cfRNA may provide vital insights into disease biology and resistance mechanisms in mCRPC.Patient summaryIn this study of men with advanced prostate cancer, DNA and RNA abnormalities in the androgen receptor detected in blood were associated with poor outcomes on available drug treatments. This information could be used to better guide treatment of advanced prostate cancer.

Project description:To provide treatment recommendations for men with metastatic castration-resistant prostate cancer (CRPC).The American Society of Clinical Oncology and Cancer Care Ontario convened an expert panel to develop evidence-based recommendations informed by a systematic review of the literature.When added to androgen deprivation, therapies demonstrating improved survival, improved quality of life (QOL), and favorable benefit-harm balance include abiraterone acetate/prednisone, enzalutamide, and radium-223 ((223)Ra; for men with predominantly bone metastases). Improved survival and QOL with moderate toxicity risk are associated with docetaxel/prednisone. For asymptomatic/minimally symptomatic men, improved survival with unclear QOL impact and low toxicity are associated with sipuleucel-T. For men who previously received docetaxel, improved survival, unclear QOL impact, and moderate to high toxicity risk are associated with cabazitaxel/prednisone. Modest QOL benefit (without survival benefit) and high toxicity risk are associated with mitoxantrone/prednisone after docetaxel. No benefit and excess toxicity are observed with bevacizumab, estramustine, and sunitinib.Continue androgen deprivation (pharmaceutical or surgical) indefinitely. Abiraterone acetate/prednisone, enzalutamide, or (223)Ra should be offered; docetaxel/prednisone should also be offered, accompanied by discussion of toxicity risk. Sipuleucel-T may be offered to asymptomatic/minimally symptomatic men. For men who have experienced progression with docetaxel, cabazitaxel may be offered, accompanied by discussion of toxicity risk. Mitoxantrone may be offered, accompanied by discussion of limited clinical benefit and toxicity risk. Ketoconazole or antiandrogens (eg, bicalutamide, flutamide, nilutamide) may be offered, accompanied by discussion of limited known clinical benefit. Bevacizumab, estramustine, and sunitinib should not be offered. There is insufficient evidence to evaluate optimal sequences or combinations of therapies. Palliative care should be offered to all patients.

Dataset Information

Clinical utility of FoundationOne tissue molecular profiling in men with metastatic prostate cancer.

Publications

Clinical utility of FoundationOne tissue molecular profiling in men with metastatic prostate cancer.

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