Androgens in Health and Disease.pdf - E Library

Chapter 9/Androgen Signaling in Prostatic Neoplasia and Hyperplasia 167
Table 1 (continued)
Ref. No. of cases No. of mutations
Stage A and B CaP 336 2 Somatic mutations,
2 germline mutations,
and 3 changes of poly Q tract
Stage C and D 238 27 Somatic mutations,
primary CaP 1 change of the poly Q tract
Metastases 97 24 Somatic mutations
Note: It should be noticed that some mutations not inserted in the table have been identified in cell
lines (139,268) and xenografts (98) derived from clinical specimens, or from the prostates of
TRAMP mice (269). The total number of cases examined is 724. In 64 of these (137), it was not
possible to deduce the disease stage from the study. Thus, the total number of prostate cancer
examined for AR mutations in which it is possible to deduce the disease state is 660. From 11 of
these patients, specimens were obtained from the primary cancer and metastatic tissue (118,127).
(See footnote below for explanation of A, B, C, and D staging system.)
Table 2
Androgen Receptor Mutations in Latent Prostate Cancer
Ref. No. of cases No. of mutations
137 74 Japanese 18
137 43 American 0
Total 117 18
DHEA, androstenedione, and androgen antagonists. These mutant ARs may be activated
by a low circulating level of androgens, resulting in the stimulation of cancer growth in
patients previously treated with antiandrogens or with conventional androgen ablation.
The functional consequences of these mutations have several implications, and they
help to explain the molecular basis of hormone refractory prostate cancer. Most patients
with metastatic cancer undergo treatments that remove testicular, but not adrenal androgens,
or they receive potentially agonistic “antiandrogens.” Prostate cancers carrying
mutations of the gain-of-function type may be resistant to these therapies. A clinical
correlate to the activation of AR by hydroxyflutamide in vitro is the so-called “flutamide
withdrawal syndrome.” These patients with advanced disease experienced an unexpected
decrease in serum prostate-specific antigen (PSA) following withdrawal of
antiandrogen treatment (142). This syndrome has now been extended to withdrawal
syndromes observed after discontinuation of nilutamide, bicalutamide (Casodex), diethylstilbestrol,
megestrol acetate, and chlormadinone acetate (143–147).
A1: Well-differentiated, impalpable lesion involving less than 5% of the gland. A2: Impalpable
microscopic disease involving more than 5% of gland. B1: Palpable nodule confined to
single lobe. B2: Palpable nodules. C: Localized but extraglandular disease. D1: Pelvic lymph
nodes involved. D2: Osseous metastases or distant spread to viscera.