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Nascent Prostate Cancer Heterogeneity Drives Evolution and Resistance to Intense Hormonal Therapy.
Wilkinson, Scott; Ye, Huihui; Karzai, Fatima; Harmon, Stephanie A; Terrigino, Nicholas T; VanderWeele, David J; Bright, John R; Atway, Rayann; Trostel, Shana Y; Carrabba, Nicole V; Whitlock, Nichelle C; Walker, Stephanie M; Lis, Rosina T; Abdul Sater, Houssein; Capaldo, Brian J; Madan, Ravi A; Gulley, James L; Chun, Guinevere; Merino, Maria J; Pinto, Peter A; Salles, Daniela C; Kaur, Harsimar B; Lotan, Tamara L; Venzon, David J; Choyke, Peter L; Turkbey, Baris; Dahut, William L; Sowalsky, Adam G.
Afiliación
  • Wilkinson S; Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, MD, USA.
  • Ye H; Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA; Department of Pathology and Department of Urology, University of California-Los Angeles, Los Angeles, CA, USA.
  • Karzai F; Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.
  • Harmon SA; Molecular Imaging Branch, National Cancer Institute, Bethesda, MD, USA; Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • Terrigino NT; Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, MD, USA.
  • VanderWeele DJ; Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, MD, USA; Department of Medicine, Feinberg School of Medicine, Chicago, IL, USA.
  • Bright JR; Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, MD, USA.
  • Atway R; Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, MD, USA.
  • Trostel SY; Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, MD, USA.
  • Carrabba NV; Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, MD, USA.
  • Whitlock NC; Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, MD, USA.
  • Walker SM; Molecular Imaging Branch, National Cancer Institute, Bethesda, MD, USA.
  • Lis RT; Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, MD, USA.
  • Abdul Sater H; Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.
  • Capaldo BJ; Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, MD, USA.
  • Madan RA; Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.
  • Gulley JL; Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.
  • Chun G; Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.
  • Merino MJ; Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA.
  • Pinto PA; Urologic Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
  • Salles DC; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • Kaur HB; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • Lotan TL; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • Venzon DJ; Biostatistics and Data Management Section, National Cancer Institute, Rockville, MD, USA.
  • Choyke PL; Molecular Imaging Branch, National Cancer Institute, Bethesda, MD, USA.
  • Turkbey B; Molecular Imaging Branch, National Cancer Institute, Bethesda, MD, USA.
  • Dahut WL; Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA.
  • Sowalsky AG; Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, MD, USA. Electronic address: adam.sowalsky@nih.gov.
Eur Urol ; 80(6): 746-757, 2021 Dec.
Article en En | MEDLINE | ID: mdl-33785256
ABSTRACT

BACKGROUND:

Patients diagnosed with high risk localized prostate cancer have variable outcomes following surgery. Trials of intense neoadjuvant androgen deprivation therapy (NADT) have shown lower rates of recurrence among patients with minimal residual disease after treatment. The molecular features that distinguish exceptional responders from poor responders are not known.

OBJECTIVE:

To identify genomic and histologic features associated with treatment resistance at baseline. DESIGN, SETTING, AND

PARTICIPANTS:

Targeted biopsies were obtained from 37 men with intermediate- to high-risk prostate cancer before receiving 6 mo of ADT plus enzalutamide. Biopsy tissues were used for whole-exome sequencing and immunohistochemistry (IHC). OUTCOME MEASUREMENTS AND STATISTICAL

ANALYSIS:

We assessed the relationship of molecular features with final pathologic response using a cutpoint of 0.05 cm3 for residual cancer burden to compare exceptional responders to incomplete and nonresponders. We assessed intratumoral heterogeneity at the tissue and genomic level, and compared the volume of residual disease to the Shannon diversity index for each tumor. We generated multivariate models of resistance based on three molecular features and one histologic feature, with and without multiparametric magnetic resonance imaging estimates of baseline tumor volume. RESULTS AND

LIMITATIONS:

Loss of chromosome 10q (containing PTEN) and alterations to TP53 were predictive of poor response, as were the expression of nuclear ERG on IHC and the presence of intraductal carcinoma of the prostate. Patients with incompletely and nonresponding tumors harbored greater tumor diversity as estimated via phylogenetic tree reconstruction from DNA sequencing and analysis of IHC staining. Our four-factor binary model (area under the receiver operating characteristic curve [AUC] 0.89) to predict poor response correlated with greater diversity in our cohort and a validation cohort of 57 Gleason score 8-10 prostate cancers from The Cancer Genome Atlas. When baseline tumor volume was added to the model, it distinguished poor response to NADT with an AUC of 0.98. Prospective use of this model requires further retrospective validation with biopsies from additional trials.

CONCLUSIONS:

A subset of prostate cancers exhibit greater histologic and genomic diversity at the time of diagnosis, and these localized tumors have greater fitness to resist therapy. PATIENT

SUMMARY:

Some prostate cancer tumors do not respond well to a hormonal treatment called androgen deprivation therapy (ADT). We used tumor volume and four other parameters to develop a model to identify tumors that will not respond well to ADT. Treatments other than ADT should be considered for these patients.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Antagonistas de Andrógenos Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Humans / Male Idioma: En Revista: Eur Urol Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Antagonistas de Andrógenos Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Humans / Male Idioma: En Revista: Eur Urol Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos