PD52-12 ANALYSIS OF THE PROGNOSTIC SIGNIFICANCE OF CIRCULATING TUMOR DNA (CTDNA) IN METASTATIC CASTRATE RESISTANT PROSTATE CANCER (MCRPC)

197 Background: Androgen receptor (AR) mutations commonly occur in metastatic castrate resistant prostate cancer (mCRPC). Methods: Circulating tumor DNA (ctDNA) data were obtained from Guardant 360 assays throughout the clinical course of mCRPC patients (pts). Retrospective analysis for any pt with ≥ 3 Guardant assays at least 4 weeks apart were reviewed. Patients must have at least 1 AR mutation or amplification to qualify for inclusion. Statistical analyses, including chi-sq and longitudinal analyses, were conducted. Results: Of the 259 patients with Guardant testing, a total of 88 patients had at least 3 Guardant tests; of these, 59 (67%) had at least one AR alteration. Patients had a median of 4 Guardant assays (range 3-10). Patients with AR amplification, AR mutation or both were identified (23, 20, 16 respectively). The most common and clinically relevant AR mutations found alone or in combination with amplification were T878A (22%), L702H(19%), W742C (19%), and H875Y (10%). These particular functional AR mutations occurred alone in 16 patients. Only 3 patients had neither amplification nor common AR mutation. 17/59 patients were found to have at least one common AR mutation and amplification at some point (on same or different Guardant). One patient had seven different AR mutations with no amplification and two other patients had 3 AR mutations. Remainder of patients had either AR amplification or ≤ 2 alternative mutations. Patients with an AR amplification were 0.1138x (95% Cl 0.0289 - 0.4491) significantly less likely of having a common known functional mutation (p <0.002) at any point. Conclusions: Patients with the most frequently identified known functional AR mutations are less likely to have AR amplification in pts with mCRPC; these common AR mutations have been shown to be associated with resistance to 2nd generation androgen deprivation. Further clinical correlation between treatment regimen and %cfDNA of these and other non-AR driver mutations is planned.

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Association of elevated serum CEA with visceral metastasis and distinctive circulating tumor DNA alterations in castrate-resistant prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e17023 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e17023-e17023

Author(s):

Alexander Bray ◽

Pannaga G. Malalur ◽

Leylah Drusbosky ◽

Theodore Stewart Gourdin ◽

Michael B. Lilly

Keyword(s):

Prostate Cancer ◽

Elevated Serum ◽

Circulating Tumor Dna ◽

Specific Gene ◽

Non Invasive ◽

Serum Carcinoembryonic Antigen ◽

Castrate Resistant Prostate Cancer ◽

Serum Cea ◽

Castrate Resistant ◽

Tumor Dna

e17023 Background: Serum carcinoembryonic antigen (CEA) is elevated in certain subtypes of castrate resistant prostate cancer (CRPC) such as aggressive variant prostate cancer (AVPC). Independent association of CEA expression with clinical stage and specific tumor gene variants could enable its use as a prognostic indicator and non-invasive biomarker of therapeutic response. Methods: Circulating tumor DNA (ctDNA) alterations in a commercially available panel of genes (Guardant Health) and serum CEA from 178 CRPC patients were retrospectively analyzed. These patients were defined as AVPC or non-AVPC based on the presence of 1 or more of the published Aparicio criteria (Aparicio et al, 2013). Clinical characteristics and ctDNA alterations were compared in patients with elevated and normal CEA. AVPC and non-AVPC patients were then compared to evaluate the uniqueness of CEA associated findings. Results: Patients with CRPC and elevated serum CEA were more likely to have liver (36.1% vs 12.0%, p = 0.002) and lung metastasis (19.4% vs 6.4%, p = 0.0441) compared to patients with normal CEA. When ctDNA profiles were analyzed there were no significant differences in rates of single nucleotide variants (SNVs) between patients with elevated and normal CEA. In contrast, patients with elevated CEA were significantly more likely to harbor copy number amplifications (CNAs) in BRAF, CDK6, FGR1, MET, CCNE1, MYC, KIT, CCND2, PIK3CA, RAF1, and KRAS. Of these, only PIK3CA and KRAS were significantly elevated in AVPC patients compared to non-AVPC patients. Relative to non-AVPC CRPC, patients with AVPC were significantly more likely to have clonal SNVs in TP53, PTEN, or RB (p = 0.0131). They were also more likely to have clonal SNVs in TP53 (p = 0.06). Conclusions: 1.) Elevated serum CEA is independently associated with visceral metastases in patients with CRPC. 2.) Elevated serum CEA in CRPC is associated with specific gene amplifications which are detectable by ctDNA analysis and not associated with AVPC as a whole. 3.) The ctDNA findings in patients with AVPC mirror previous tissue-based studies which documented recurrent genetic variations in TP53, PTEN, and RB (Aparicio et al, 2016). Together these findings outline a potential role for ctDNA profiling and serum CEA as non-invasive biomarkers in CRPC. They also suggest that elevated serum CEA may be associated with a genetically distinct subtype of AVPC.

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Clinical and genomic insights into circulating tumor DNA-based alterations across the spectrum of metastatic hormone-sensitive and castrate-resistant prostate cancer

EBioMedicine ◽

10.1016/j.ebiom.2020.102728 ◽

2020 ◽

Vol 54 ◽

pp. 102728 ◽

Cited By ~ 3

Author(s):

Manish Kohli ◽

Winston Tan ◽

Tiantian Zheng ◽

Amy Wang ◽

Carlos Montesinos ◽

...

Keyword(s):

Prostate Cancer ◽

Circulating Tumor Dna ◽

Castrate Resistant Prostate Cancer ◽

Hormone Sensitive ◽

Castrate Resistant ◽

Tumor Dna

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Analysis of the prognostic significance of circulating tumor DNA (ctDNA) in metastatic castrate-resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.110 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 110-110

Author(s):

Justin Shaya ◽

James Michael Randall ◽

Frederick E. Millard ◽

Razelle Kurzrock ◽

J Kellogg Parsons ◽

...

Keyword(s):

Tumor Suppressor ◽

Prognostic Significance ◽

Median Number ◽

Circulating Tumor Dna ◽

Time To Progression ◽

Genomic Alterations ◽

Visceral Metastases ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant ◽

Allelic Fraction

110 Background: Given the technical limitations of obtaining tissue next-generation sequencing, there has been interest in blood ctDNA to assess genomic alterations in mCRPC. We examined the genomic landscape and prognostic significance of ctDNA in mCRPC. Methods: Single center retrospective analysis of mCRPC patients who underwent ctDNA genomic profiling using Guardant360. Overall survival (OS) and time to progression (TTP) were examined and stratified by the presence of tumor suppressor mutations (p53, PTEN, Rb), androgen receptor (AR) amplification or mutation, number of genomic alterations, and highest allelic fraction of detected mutations. Results: At the time of ctDNA collection, all patients (n=46) had mCRPC with bone metastases present in 100% of patients and visceral metastases present in 17.3%. Median age at ctDNA collection was 71 years, median time from CRPC diagnosis to ctDNA was 13 months (range 0-45), and median follow-up time from CRPC diagnosis was 17.5 months (4-40). The most common alterations present were TP53 mutation (41.3%), AR amplification (30.4%), and CDK6 amplification (21.7%). Actionable mutations were detected in BRCA1 (4.3%), BRCA2 (4.3%), ATM (2.2%), and PMS2 (2.2%). The median number of genomic alterations was 2 (0-8) and the median ctDNA allelic fraction was 4.6% (0-86.9%). Median OS of the cohort was 36 months. The presence of a tumor suppressor mutation, > 2 genomic alterations, and >5% mutation allelic fraction was associated with inferior OS (Table). In terms of time to progression on 1st line abiraterone or enzalutamide, the presence of an AR amplification or mutation was associated with significantly worse median TTP of 6.9 vs 13.5 months ( p- 0.015). Conclusions: ctDNA is frequently detected in mCRPC; and the type, number and frequency of alterations are potentially prognostic of OS in mCRPC. Ongoing studies are needed to assess concordance of ctDNA with tissue NGS and the predictability of ctDNA.[Table: see text]

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