Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer

Annala, Matti; Vandekerkhove, Gillian; Khalaf, Daniel; Taavitsainen, Sinja; Beja, Kevin; Warner, Evan W.; Sunderland, Katherine; Kollmannsberger, Christian; Eigl, Bernhard J.; Finch, Daygen L.; Oja, Conrad D.; Vergidis, Joanna; Zulfiqar, Muhammad; Azad, Arun; Nykter, Matti; Gleave, Martin; Wyatt, Alexander W.; N., Kim

doi:10.1158/2159-8290.cd-17-0937

Cited by 388 publications

(519 citation statements)

References 44 publications

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“…This is exemplified by the most frequently observed therapy-associated alteration, i.e. the AR amplification, which alone appears to be unreliable as a predictive marker for response to treatment with abiraterone or enzalutamide, an observation recently also reported by others 42, 57 . Another limitation concerns the heterogeneity of the cohort regarding different pretreatments.…”

Section: Discussionmentioning

confidence: 87%

“…After submission of our manuscript, a paper was published describing ctDNA analyses during a trial in which patients were randomized to treatment with abiraterone or enzalutamide 57 . Similar to our observations, the authors did not detect a prognostic effect of AR amplification but discuss the possibility of poorer response for patients with high AR copy number (>8).…”

Section: Discussionmentioning

confidence: 99%

“…Similar to our observations, the authors did not detect a prognostic effect of AR amplification but discuss the possibility of poorer response for patients with high AR copy number (>8). Otherwise, alterations in BRCA2 , ATM , and TP53 were associated with poor clinical outcome 57 .…”

Section: Discussionmentioning

confidence: 99%

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Genomic alterations in plasma DNA from patients with metastasized prostate cancer receiving abiraterone or enzalutamide

Belic

Graf

Bauernhofer

et al. 2018

Intl Journal of Cancer

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In patients with metastatic castrate resistant prostate cancer (mCRPC), circulating tumor DNA (ctDNA) analysis offers novel opportunities for the development of non-invasive biomarkers informative of treatment response with novel agents targeting the androgen-receptor (AR) pathway, such as abiraterone or enzalutamide. However, the relationship between ctDNA abundance, detectable somatic genomic alterations and clinical progression of mCRPC remains unexplored. Our study aimed to investigate changes in plasma DNA during disease progression and their associations with clinical variables in mCRPC patients. We analyzed ctDNA in two cohorts including 94 plasma samples from 25 treatment courses (23 patients) and 334 plasma samples from 125 patients, respectively. We conducted whole-genome sequencing (plasma-Seq) for genome-wide profiling of somatic copy number alterations and targeted sequencing of 31 prostate cancer-associated genes. The combination of plasma-Seq with targeted AR analyses identified prostate cancer-related genomic alterations in 16 of 25 (64%) treatment courses in the first cohort, in which we demonstrated that AR amplification does not always correlate with poor abiraterone and enzalutamide therapy outcome. As we observed a wide variability of ctDNA levels, we evaluated ctDNA levels and their association with clinical parameters and included the second, larger cohort for these analyses. Employing altogether 428 longitudinal plasma samples from 148 patients, we identified the presence of bone metastases, increased lactate dehydrogenase and prostate-specific antigen (PSA) as having the strongest association with high ctDNA levels. In summary, ctDNA alterations are observable in the majority of patients with mCRPC and may eventually be useful to guide clinical decision-making in this setting.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

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Genomic alterations in plasma DNA from patients with metastasized prostate cancer receiving abiraterone or enzalutamide

Belic

Graf

Bauernhofer

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

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“…Novel AR antagonists may be able to target growth mediated by AR mutations (eg, darolutamide delayed the growth of enzalutamide‐resistant prostate cancer harboring mutated AR in a preclinical system) . BRCA2 , ATM , and TP53 ctDNA mutations also have been associated with rapid resistance in the setting of enzalutamide or abiraterone …”

Section: Discussionmentioning

confidence: 99%

Circulating tumor DNA alterations in patients with metastatic castration‐resistant prostate cancer

Sonpavde

Agarwal

Pond

et al. 2019

Cancer

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Background Because cell‐free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration‐resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy. Methods Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer‐associated genes. Clinical factors, therapy information, failure‐free survival, and overall survival (OS) were obtained for select patients. The association between genomic alterations and outcomes was investigated. Results Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta‐1 (CTNNB1), and AT‐rich interactive domain‐containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure‐free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes. Conclusions ctDNA frequently was detected in this large cohort of “real‐world” patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected patients.

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“…To overcome this limitation, it is essential to develop highly sensitive and reproducible detection methods to identify ctDNA. Methodologies for detecting ctDNA are shown in Table …”

Section: Development Of Approaches For Detection Of Ctdnamentioning

confidence: 99%

Clinical utility of circulating tumor DNA for colorectal cancer

et al. 2019

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Colorectal cancer (CRC) is currently the most common type of cancer in Japan, and its prognosis has improved because of development of diagnosis and advancement in treatments including surgery and chemotherapy. However, because of intratumor heterogeneity and clonal evolution, tumors often develop resistance to treatment. Genotyping tumor tissue in search of somatic genetic alterations for actionable information has become routine examination in clinical practice. However, the inherent molecular heterogeneity of metastatic tumors and the ability of cancer genomes to dynamically evolve are not properly captured by tissue specimens only. Circulating tumor DNA (ctDNA) carrying tumor‐specific genetic or epigenetic alterations is released into the circulation from tumor cells undergoing apoptosis or necrosis. Analysis of ctDNA has the potential to change clinical practice by exploiting blood rather than tissue, as a source of information. Here, we provide an overview of the characteristics of ctDNA and focus on detection methods for ctDNA, and the feasibility of use of ctDNA to monitor tumor dynamics for patients with colorectal cancer.

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Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer

Cited by 388 publications

References 44 publications

Genomic alterations in plasma DNA from patients with metastasized prostate cancer receiving abiraterone or enzalutamide

Genomic alterations in plasma DNA from patients with metastasized prostate cancer receiving abiraterone or enzalutamide

Circulating tumor DNA alterations in patients with metastatic castration‐resistant prostate cancer

Clinical utility of circulating tumor DNA for colorectal cancer

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