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Circulating Tumor Cell Genomic Evolution and Hormone Therapy Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer.

Publication ,  Conference
Gupta, S; Halabi, S; Kemeny, G; Anand, M; Giannakakou, P; Nanus, DM; George, DJ; Gregory, SG; Armstrong, AJ
Published in: Molecular cancer research : MCR
June 2021

Men with circulating tumor cell (CTC) AR-V7-positive metastatic castration-resistant prostate cancer (mCRPC) have worse outcomes when treated with enzalutamide/abiraterone. However, most men lack CTC AR-V7 detection, and additional predictive biomarkers are needed. We conducted a retrospective secondary analysis of the prospective PROPHECY trial (NCT02269982) of men with mCRPC undergoing treatment with enzalutamide/abiraterone, analyzing pooled CTC and germline DNA for whole-genome copy-number alterations (CNA) in 73 samples from 48 men over time along with pooled CTC and germline whole-exome sequencing on 22 paired samples before and following progression on androgen receptor (AR) inhibitor therapy to identify somatic genomic alterations associated with acquired resistance. We observed broad interpatient and longitudinal CTC genomic heterogeneity from AR-V7-negative men with mCRPC, including common gains of KDM6A, MYCN, and AR, and loss of ZFHX3, BRCA1, and PTEN. Men who had progression-free survival of ≤3 months despite enzalutamide/abiraterone treatment were more likely to have baseline CTC genomic loss of CHD1, PTEN, PHLPP1, and ZFHX3 and gains of BRCA2, KDM5D, MYCN, and SPARC. After progression on abiraterone/enzalutamide, we observed clonal evolution of CTCs harboring TP53 mutations and gain of ATM, KDM6A, and MYC, and loss of NCOR1, PTEN, RB1, and RUNX2. CTC genomic findings were independently confirmed in a separate cohort of mCRPC men who progressed despite prior treatment with abiraterone/enzalutamide (NCT02204943). IMPLICATIONS: We identified common and reproducible genomic alterations in CTCs from AR-V7-negative mCRPC men associated with poor outcomes during enzalutamide/abiraterone treatment, including CNAs in genes linked to lineage plasticity and epigenetic signaling, DNA repair, AR, TP53/RB1, PTEN, and WNT pathways.

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Published In

Molecular cancer research : MCR

DOI

EISSN

1557-3125

ISSN

1541-7786

Publication Date

June 2021

Volume

19

Issue

6

Start / End Page

1040 / 1050

Related Subject Headings

  • Treatment Outcome
  • Retrospective Studies
  • Receptors, Androgen
  • Protein Isoforms
  • Prostatic Neoplasms, Castration-Resistant
  • Phenylthiohydantoin
  • Oncology & Carcinogenesis
  • Nitriles
  • Neoplastic Cells, Circulating
  • Neoplasm Metastasis
 

Citation

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Chicago
ICMJE
MLA
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Gupta, S., Halabi, S., Kemeny, G., Anand, M., Giannakakou, P., Nanus, D. M., … Armstrong, A. J. (2021). Circulating Tumor Cell Genomic Evolution and Hormone Therapy Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer. In Molecular cancer research : MCR (Vol. 19, pp. 1040–1050). https://doi.org/10.1158/1541-7786.mcr-20-0975
Gupta, Santosh, Susan Halabi, Gabor Kemeny, Monika Anand, Paraskevi Giannakakou, David M. Nanus, Daniel J. George, Simon G. Gregory, and Andrew J. Armstrong. “Circulating Tumor Cell Genomic Evolution and Hormone Therapy Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer.” In Molecular Cancer Research : MCR, 19:1040–50, 2021. https://doi.org/10.1158/1541-7786.mcr-20-0975.
Gupta S, Halabi S, Kemeny G, Anand M, Giannakakou P, Nanus DM, et al. Circulating Tumor Cell Genomic Evolution and Hormone Therapy Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer. In: Molecular cancer research : MCR. 2021. p. 1040–50.
Gupta, Santosh, et al. “Circulating Tumor Cell Genomic Evolution and Hormone Therapy Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer.Molecular Cancer Research : MCR, vol. 19, no. 6, 2021, pp. 1040–50. Epmc, doi:10.1158/1541-7786.mcr-20-0975.
Gupta S, Halabi S, Kemeny G, Anand M, Giannakakou P, Nanus DM, George DJ, Gregory SG, Armstrong AJ. Circulating Tumor Cell Genomic Evolution and Hormone Therapy Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer. Molecular cancer research : MCR. 2021. p. 1040–1050.

Published In

Molecular cancer research : MCR

DOI

EISSN

1557-3125

ISSN

1541-7786

Publication Date

June 2021

Volume

19

Issue

6

Start / End Page

1040 / 1050

Related Subject Headings

  • Treatment Outcome
  • Retrospective Studies
  • Receptors, Androgen
  • Protein Isoforms
  • Prostatic Neoplasms, Castration-Resistant
  • Phenylthiohydantoin
  • Oncology & Carcinogenesis
  • Nitriles
  • Neoplastic Cells, Circulating
  • Neoplasm Metastasis