Personalized Prediction of Tumor Response and Cancer Progression on Prostate Needle Biopsy

Received 18 December 2008 published online 18 May 2009.

Refers to article:

Phase II Trial of Capecitabine and Weekly Docetaxel for Metastatic Castrate Resistant Prostate Cancer , 18 May 2009
Ulka N. Vaishampayan, Shanthi Marur, Lance K. Heilbrun, Michael L. Cher, Brenda Dickow, Daryn W. Smith, Samir A. Al Hasan, James Eliason
The Journal of Urology
July 2009 (Vol. 182, Issue 1, Pages 317-323)
Abstract | Full Text | Full-Text PDF (480 KB)

Purpose

To our knowledge in patients with prostate cancer there are no available tests except clinical variables to determine the likelihood of disease progression. We developed a patient specific, biology driven tool to predict outcome at diagnosis. We also investigated whether biopsy androgen receptor levels predict a durable response to therapy after secondary treatment.

Materials and Methods

We evaluated paraffin embedded prostate needle biopsy tissue from 1,027 patients with cT1c-T3 prostate cancer treated with surgery and followed a median of 8 years. Machine learning was done to integrate clinical data with biopsy quantitative biometric features. Multivariate models were constructed to predict disease progression with the C index to estimate performance.

Results

In a training set of 686 patients (total of 87 progression events) 3 clinical and 3 biopsy tissue characteristics were identified to predict clinical progression within 8 years after prostatectomy with 78% sensitivity, 69% specificity, a C index of 0.74 and a HR of 5.12. Validation in an independent cohort of 341 patients (total of 44 progression events) yielded 76% sensitivity, 64% specificity, a C index of 0.73 and a HR of 3.47. Increased androgen receptor in tumor cells in the biopsy highly significantly predicted resistance to therapy, ie androgen ablation with or without salvage radiotherapy, and clinical failure (p <0.0001).

Conclusions

Morphometry reliably classifies Gleason pattern 3 tumors. When combined with biomarker data, it adds to the hematoxylin and eosin analysis, and prostate specific antigen values currently used to assess outcome at diagnosis. Biopsy androgen receptor levels predict the likelihood of a response to therapy after recurrence and may guide future treatment decisions.

Key Words: prostate, prostatic neoplasms, biopsy, receptors, androgen, biological markers

Abbreviations and Acronyms: AMACR, α-methyl-acyl-coenzyme A racemase, AR, androgen receptor, bGG, dominant biopsy Gleason grade, bGS, biopsy Gleason sum, CF, clinical failure, CK18, cytokeratin 18, FP, favorable pathology, MST, minimal spanning tree, pAKT, phosphorylated, SVRc, censored data support vector regression

a Aureon Laboratories, Inc., New York, New York

b Yonkers and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York

c Center for Bioinformatics and Molecular Biostatistics, University of California-San Francisco, San Francisco, California

d Mayo Clinic, Rochester, Minnesota

e University Hospital at Uppsala, Uppsala, Sweden

f Durham Veterans Affairs and Duke University Medical Center, Durham, North Carolina

g University of Connecticut Health Science Center, Farmington, Connecticut

h Yale University School of Medicine, New Haven, Connecticut

Correspondence: Aureon Laboratories, Inc., 28 Wells Ave., Yonkers, New York 10701 (telephone: 914-377-4037; FAX: 914-377-4001)

Study received Durham Veterans Affairs Medical Center, Mayo Clinic, University of Connecticut Health Science Center, University of Graz and University Hospital at Uppsala institutional review board approval.

Supported by an Aureon Laboratories sponsored research agreement.

Supplementary material for this article can be obtained at jason.alter@aureon.com.

For another article on a related topic see page 317.

† Financial interest and/or other relationship with Aureon Laboratories.

‡ Financial interest and/or other relationship with Sanofi, Bristol Meyers, Galaxo and Blue Cross Blue Shield.

PII: S0022-5347(09)00570-9

doi:10.1016/j.juro.2009.02.135

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