Labrie F, Cusan L, Gomez JL, Diamond P, Candas B
Prostate Cancer Research Unit, CHUL Research Center, Le Centre Hospitalier de l'Universite Laval, Quebec, Canada.
J Clin Endocrinol Metab 1995 Jul;80(7):2002-13

Prostate cancer is the second cause of cancer death in men in the Western world; its medical and social impact is comparable to that of breast cancer in women. Although it is well recognized that early treatment is the only possibility for reducing the high rate of death from prostate cancer, screening and even early treatment are controversial issues due mainly to arguments based upon old literature and lack of awareness of the significant advances recently made in this field. As it is well known that surgical removal of organ-confined prostate cancer cures the disease, and it has been demonstrated that annual screening with prostate-specific antigen coupled with digital rectal examination followed, when indicated, by transrectal ultrasonography of the prostate more than doubles the proportion of organ-confined disease, screening alone offers the possibility of at least doubling the number of patients curable from prostate cancer or the potential for a cure to an estimated 45% of prostate cancer patients compared to a maximum of 20% in the absence of screening. It is important to mention that screening does not detect small and insignificant cancers, especially when random biopsies are not performed routinely. The critical volume of prostate cancer is estimated at 0.3 cm or a tumor 7.5 mm in diameter, if spherical. Such a tumor should increase serum prostate-specific antigen by 0.5 ng/mL. Contrary to the belief that screening detects cancers that are too small, the fact is that screening detects prostate cancer too late or nonorgan- or nonspecimen-confined cancer in 35-50% of cases. There is, thus, a narrow window when prostate cancer can be detected at a curable stage, and even the best available screening techniques cannot succeed in all cases. It should be mentioned that the recent improvements of the technique of radical prostatectomy have markedly improved the acceptability of surgery. Concerning the recent publicity related to watchful waiting, it is essential to indicate that all such reports support the notion that prostate cancer grows slowly, but steadily and irremediably, with increasing malignancy and risk of distant metastases and death if sufficient time is allowed. Another serious limitation of watchful waiting is that the available prognostic factors have a large margin of error and cannot predict with certainty the rate of progression of the tumor.

Labrie F, Candas B, Cusan L, Gomez JL, Diamond P, Suburu R, Lemay M
Prostate Cancer Clinical Research Unit, CHUL Research Center, Quebec, Canada.
Urology 1996 Feb;47(2):212-7

OBJECTIVES: To determine the percentage of localized and potentially curable prostate cancers diagnosed at follow-up screening visits compared with the first screening visit.

METHODS: Within the context of a prospective screening study performed in randomly chosen men aged between 45 and 80 years, up to 6-year follow-up screening visits have been performed with serum prostate-specific antigen (PSA) measurement and digital rectal examination (DRE) followed by transrectal ultrasonography of the prostate when PSA or DRE is abnormal.

RESULTS: Of the 117 prostate cancers diagnosed at 14,554 annual follow-up visits, only 1 cancer (0.9%) was metastatic compared with 8% (26/322) at 8029 first visits. Moreover, 97% of the cancers detected at follow-up visits could be identified by PSA alone compared with 86% at first visit. The incidence of 0.8% per year during 15 years of screening between the ages of 55 and 70 years would diagnose localized prostate cancer in 12% of the population, a value not too different from the 10% diagnosed with prostate cancer during life-time in the absence of screening.

CONCLUSIONS: The present data show that annual screening with PSA diagnoses clinically localized prostate cancer in more than 95% of cases, thus almost completely eliminating the diagnosis of metastatic prostate cancer. Moreover, the number of prostate cancers diagnosed is not significantly increased by screening.

Babaian RJ, Fritsche HA, Zhang Z, Zhang KH, Madyastha KR, Barnhill SD
Department of Urology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Urology 1998 Jan;51(1):132-136

OBJECTIVES: Although prostate-specific antigen (PSA) has revolutionized the detection of prostate cancer, it has definite limitations with respect to its clinical sensitivity and specificity. Because a substantial number (20% to 40%) of men undergoing radical prostatectomy have a PSA level of 4.0 ng/mL or less, any new test offering diagnostic improvement must perform well in patients whose PSA level is less than or equal to 4.0 ng/mL, as well as in patients whose PSA is greater than 4.0 ng/mL. The performances of two tests, the ProstAsure index and the percent free PSA test, were evaluated in detecting cancer.

METHODS: We retrospectively analyzed serum samples from 225 men who were grouped into three categories: 94 men who had a normal digital rectal examination and a serum PSA level of 4.0 ng/mL or less, 77 men who were clinically suspected of having benign prostatic hyperplasia (BPH) with a serum PSA level of 4.0 ng/mL or less, and 54 men with localized prostate cancer. The PSA assays were performed using the Hybritech and Tosoh assays and the ProstAsure index was determined by Global Health Net, Savannah, Ga. Receiver operator characteristic (ROC) curves were constructed to evaluate the performance of these two tests, and the areas under the curve were compared for significance.

RESULTS: The sensitivity and specificity of detecting prostate cancer using ProstAsure were 93% and 81%, respectively. Using a cutoff value of 15%, the sensitivity and specificity of detecting cancer for percent free PSA were 80% and 74%, respectively (sensitivity increased to 93% and specificity to 59% for free PSA at 19%). In men with a total serum PSA level of 4.0 ng/mL or less, ProstAsure had a lower false-positive rate compared to free PSA level at 19% for men with or without clinical BPH as well as for men without clinical BPH using a 15% free PSA threshold. ProstAsure left fewer cancers undetected (7%) compared to free PSA at the 15% cutoff (20%).

CONCLUSIONS: In this study of selected men, ROC curve analysis shows a statistically significant advantage in performance (P = 0.0023) for the ProstAsure index compared to free PSA in detecting prostate cancer.

Catalona WJ, Smith DS, Ornstein DK
Division of Urologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Mo 63110, USA.
JAMA 1997 May 14;277(18):1452-5

OBJECTIVE: To determine the detection rate of prostate cancer in a screening population of men with prostate-specific antigen (PSA) concentrations of 2.6 to 4.0 ng/mL and a benign prostate examination, to assess the clinicopathological features of the cancers detected, and to assess the usefulness of measuring the ratio of free to total PSA to reduce the number of prostatic biopsies.

DESIGN: A community-based study of serial screening for prostate cancer with serum PSA measurements and prostate examinations.

SETTING: University medical center.

SUBJECTS: A total of 914 consecutive screening volunteers aged 50 years or older with serum PSA levels of 2.6 to 4.0 ng/mL who had a benign prostate examination and no prior screening tests suspicious for prostate cancer, 332 (36%) of whom underwent biopsy of the prostate.

MAIN OUTCOME MEASURES: Cancer detection rate, clinical and pathological features of cancers detected, and specificity for cancer detection using measurements of percentage of free PSA.

RESULTS: Cancer was detected in 22% (73/332) of men who underwent biopsy. All cancers detected were clinically localized, and 81% (42/52) that were surgically staged were pathologically organ confined. Ten percent of the cancers were clinically low-volume and low-grade tumors, and 17% of those surgically staged were low-volume and low-grade or moderately low-grade tumors (possibly harmless). Using a percentage of free PSA cutoff of 27% or less as a criterion for performing prostatic biopsy would have detected 90% of cancers, avoided 18% of benign biopsies, and yielded a positive predictive value of 24% in men who underwent biopsy.

CONCLUSIONS: There is an appreciable rate of detectable prostate cancer in men with serum PSA levels of 2.6 to 4.0 ng/mL. The great majority of cancers detected have the features of medically important tumors. Free serum PSA measurements may reduce the number of additional biopsies required by the lower PSA cutoff.

Harris CH, Dalkin BL, Martin E, Marx PC, Ahmann FR
Section of Urology, University of Arizona College of Medicine and Tucson Veterans Affairs Medical Center, USA.
J Urol 1997 May;157(5):1740-3

PURPOSE: We evaluated the 3-year longitudinal changes in serial serum prostate specific antigen (PSA) levels in men with an initial PSA of 4.0 ng./ml. or less and no suspicion of prostate cancer.

MATERIALS AND METHODS: A total of 760 men with an initial PSA of 4.0 ng./ml. or less plus a normal or suspicious digital rectal examination and a benign prostate biopsy was enrolled into an every 4-month PSA monitoring study.

RESULTS: Of the 559 men with an initial PSA of 2.0 ng./ml. or less only 3 (0.5%) had a persistently abnormal PSA for 3 years and 1 cancer (0.2%) was detected, and 48 men had a PSA velocity of 0.8 ng./ml. per year or more at year 1 but only 1 (2%) had a persistent rate of increase (2.4 ng./ml. per year) at 3 years. Of the 201 men with a PSA of 2.1 to 4.0 ng./ml. 85 had an abnormal PSA but only 37 (43%) met the criteria for biopsy. Only 8 of 23 biopsies (35%) revealed cancer. Of the 201 men 24 had a PSA velocity of 0.8 ng./ml. Per year or more at year 1 but only 4 had persistence for 3 years. All 4 men had cancer but they were identified as at high risk by PSA criteria.

CONCLUSIONS: Men with a PSA of 2.0 ng./ml. or less are at low risk for an abnormal PSA or cancer within 3 years and annual monitoring may not be necessary. However, annual monitoring is clinically useful in men with an initial PSA of 2.1 to 4.0 ng./ml. Also, serial monitoring with interval testing in men whose PSA becomes greater than 4.0 ng./ml. is beneficial in identifying a high risk group requiring biopsy. Finally, PSA velocity did not add further to cancer detection in this population.

Eskew LA, Bare RL, McCullough DL
Department of Urology, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina, USA.
J Urol 1997 Jan;157(1):199-202; discussion 202-3

PURPOSE: The number of patients undergoing prostate biopsy has dramatically increased due to prostate specific antigen screening. The low specificity of this screening tool requires prostate biopsy for diagnosis of prostate cancer. The sextant biopsy technique has been used widely with success in diagnosing carcinoma of the prostate. However, concern has arisen that the original sextant method may not include an adequate sampling of the prostate. For many years we have used a method of prostate biopsy that, in addition to sextant biopsies, takes additional biopsies in a systematic fashion, which we call the 5 region prostate biopsy. We conducted a prospective study to determine if our 5 region prostate biopsy technique significantly increases the chances of finding carcinoma of the prostate compared to the sextant biopsy technique.

MATERIALS AND METHODS: A total of 119 patients underwent transrectal ultrasound guided needle biopsy of the prostate. In addition to sextant biopsies, cores were taken from the far lateral and mid regions of the gland. Pathological findings of the additional regions were compared to those of the sextant regions.

RESULTS: Of the 48 patients with prostate cancer 17 (35%) had carcinomas only in the additional regions, which would have remained undetected had the sextant biopsy technique been used alone (p < 0.05). Of these additional cancers 83% had Gleason scores of 6 or more.

CONCLUSIONS: We introduce the 5 region technique of prostate biopsy as a means of significantly increasing the diagnostic yield of prostate biopsy in finding carcinoma of the prostate. We have found this technique to be safe, efficacious and superior to the sextant method of biopsy in identifying prostate cancer at an early but significant stage. The greatest use of the 5 region biopsy technique is in patients who have prostate specific antigen levels between 4 and 10 ng./ml.

Aihara M, Wheeler TM, Ohori M and Scardino PT
Urology 43:60-4, 1994.

OBJECTIVE. To understand the morphologic and spatial relationships of the various grades of prostate cancer, we investigated whether poorly differentiated cancer usually arises within the center of a large, well-differentiated tumor or more often forms the periphery or leading edge of the tumor.

METHODS. In a series of one hundred and one completely sectioned whole-mount radical prostatectomy specimens removed from patients with clinical Stage T2 prostate cancer, we mapped the distribution of each of the five Gleason grades and assessed their frequency, proportion, and spatial distribution.

RESULTS. The average number of different grades present in our patients was 2.7 (range 1-5). Over 50 percent of the prostates contained at least three different grades of cancer. The number of different Gleason grades present increased significantly with increasing tumor volume (p < 0.0001). Only 10 percent of the index cancers (largest tumor present) were composed of a single grade and these cancers were small (0.02-1.7 cm3). Among cancers with multiple grades, the most common finding (53%) was a high-grade cancer present within the core of a larger, more well-differentiated tumor; however, the opposite pattern, low-grade cancer present within a larger poorly differentiated cancer, was also common (30%) and predominated in very large cancers (> 10 cm3).

CONCLUSION. Small prostate cancers are often composed of a single grade, usually Gleason grade 2 or 3. But most palpable cancers contain multiple grades which are arranged in heterogeneous and unpredictable geographic interrelationships.

Brawn PN
Cancer 1983 Jul 15;52(2):246-51

Fifty-four patients with prostate carcinoma, each having 2 TURP (transurethral resection of the prostate) procedures separated by 3 to 11 years, were studied to determine whether the histologic appearance of prostate carcinoma remains the same for the life of the host or whether the histological appearance changes with time. Using the M. D. Anderson (MDAH) method of grading prostate carcinoma, 19 of 26 (73%) Grade 1 lesions, 9 of 12 (75%) Grade 2 lesions, and 7 of 8 (88%) Grade 3 lesions dedifferentiated into another grade at the time of the 2nd TURP. Eight cases that were Grade 4 at the time of the 1st TURP, remained Grade 4 lesions at the time of the 2nd TURP. Although 10 Grade 1, Grade 2, and Grade 3 lesions did not change grades, 8 of these 10 cases were less differentiated at the time of the second TURP than they were at the time of the first TURP. Furthermore, no Grade 1 lesions demonstrated evidence of metastases, but 19% of Grade 2 lesions, 55% of Grade 3 lesions, and 80% of Grade 4 lesions demonstrated evidence of metastases. This study suggests that the usual course of prostate carcinoma is dedifferentiation and that with dedifferentiation, the likelihood of metastases increases.

Lehr JE, Pienta KJ, Yamazaki K, Pilat MJ
University of Michigan Comprehensive Cancer Center, Ann Arbor 48109-0946, USA.
Cell Mol Biol (Noisy-le-grand) 1998 Sep;44(6):949-59

Normal rat prostate epithelial cells (EPYP-1) were isolated and immortalized with the Simian Virus-40 (SV40) large T-antigen, and transfected with the v-H-ras (EPYP-1-ras) and the c-myc oncogenes (EPYP-1-myc; EPYP-1-ras-myc) to serially create a step-wise model of tumor development in the rat prostate. Pronounced morphological differences were observed between EPYP-1 and the transfected sublines. The immortal epithelial cells (EPYP-1) maintained a cuboidal shape with orderly, contact mediated inhibition of growth. Oncogene transfected clones displayed a spindle shaped structure with multiple overlapping pseudopodia. Transfected cells also exhibited a greater degree of dysplasia, loss of contact inhibition growth and the upregulation of an epithelial tumor marker, cytokeratin-18. All cells exhibited anchorage independent and androgen independent growth. In vivo, EPYP-1 cells and EPYP-1-myc and formed slowly growing non-metastatic, benign tumors in immune compromised mice, while EPYP-1-ras and EPYP-1-ras-myc transfected cells produced rapidly growing, malignant tumors in similar animals. This model augments the hypothesis that tumor initiation and progression can be caused by as few as two discrete genetic events. In addition, the "normal" rat prostate epithelium and transfected daughter cell lines represent a tumor model system with distinct, well understood genetic alterations: activation of ras and myc. This model will be a valuable addition to the current cell lines used in the investigation of prostate cancer carcinogenesis.

Yamazaki H, Sinha BK
Proc Annu Meet Am Assoc Cancer Res 34:A2309, 1993.

No abstract.

McDonnell TJ, Troncoso P, Brisbay SM, Logothetis C, Chung LW, Hsieh JT, Tu SM, Campbell ML
Department of Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Cancer Res 1992 Dec 15;52(24):6940-4

The significance of apoptosis in relation to the development and progression of prostate cancer remains largely undefined. bcl-2 is an oncogene that functions by overriding apoptosis. bcl-2 expression was localized to the basal epithelial cells in the normal human prostate with the use of immunohistochemistry. Androgen-dependent and androgen-independent prostate carcinomas were evaluated immunohistochemically for bcl-2 expression. bcl-2 was undetectable in 13 of 19 cases of androgen-dependent cancers. In contrast, androgen-independent cancers displayed diffuse, high levels of bcl-2 staining (P < 0.01). In rats, steady-state levels of bcl-2 mRNA, assessed by S1 assays, reached maximum levels 10 days following castration. Addition of exogenous testosterone with, or without, flutamide demonstrated that the increased bcl-2 Mrna resulted from androgen ablation. Our findings indicate that bcl-2 expression is augmented following androgen ablation and is correlated with the progression of prostate cancer from androgen dependence to androgen independence.

Bookstein R, MacGrogan D, Hilsenbeck SG, Sharkey F, Allred DC
Department of Molecular Biology, Canji, Inc., San Diego, California 92121.
Cancer Res 1993 Jul 15;53(14):3369-73

Inactivation of p53, a tumor suppressor gene, contributes to the genesis and/or progression of a substantial fraction of all human cancers, including > or = 50% of breast, lung, and colon carcinomas. Mutated p53 alleles typically contain missense single-base substitutions within exons 5-8 and encode abnormally stable p53 proteins that accumulate to high levels in tumor cell nuclei. To evaluate the frequency, type, and clinical significance of p53 mutation in human prostate cancer, archival tumor material from 150 prostate cancer patients was examined by immunohistochemistry (IHC) with anti-p53 antibodies. Abnormal nuclear p53 accumulation (IHC) was observed in 19 tumors (12.7%) and was strongly related to disease stage (23% of 69 stage III or IV tumors were IHC+ versus 4% of 74 stage 0-II tumors; P < 0.001, Fisher's exact test). The methods of polymerase chain reaction, single-strand conformational polymorphism, and direct sequencing were used to identify mutations, predominantly missense single-base substitutions in exons 5, 7, or 8 in 9 of 14 IHC+ cases but in none of 20 IHC- cases; 5 of these mutations were G:C-->A:T transitions at CpG dinucleotides. These data indicate that mutated p53 alleles are quite uncommon in early prostate cancers but are found in 20-25% of advanced cancers, suggesting a role for p53 mutation in the progression of at least a subset of prostate cancers.

Veldscholte J, Ris-Stalpers C, Kuiper GG, Jenster G, Berrevoets C, Claassen E, van Rooij HC, Trapman J, Brinkmann AO, Mulder E
Department of Biochemistry II, Erasmus University Rotterdam, The Netherlands.
Biochem Biophys Res Commun 1990 Dec 14;173(2):534-40

LNCaP prostate tumor cells contain an abnormal androgen receptor system. Progestagens, estradiol and anti-androgens can compete with androgens for binding to the androgen receptor and can stimulate both cell growth and excretion of prostate specific acid phosphatase. We have discovered in the LNCaP androgen receptor a single point mutation changing the sense of codon 868 (Thr to Ala) in the ligand binding domain. Expression vectors containing the normal or mutated androgen receptor sequence were transfected into COS or Hela cells. Androgens, progestagens, estrogens and anti-androgens bind the mutated androgen receptor protein and activate the expression of an androgen-regulated reporter gene construct (GRE-tk-CAT). The mutation therefore influences both binding and the induction of gene expression by different steroids and antisteroids.

Sciarra F, Sorcini G, Di Silverio F, et al:
Clin Endocrinol 2:101-109, 1973.

Instituo di Patologia Speciale Medica e Metodologia Clinica II, and *Clinica Urologica, University of Rome, Italy

Orchiectomy is often used in the management of metastatic adenocarcinoma of the prostate, an androgen dependent tumour, since it markedly reduces the concentrations of plasma testosterone (to a mean level of 28 ± 16 (SD) ng/100 ml) and temporarily inhibits the growth of the neoplasm.

In some orchiectomized patients, however, the values of plasma testosterone and androstenedione do not drop to these levels, but remain higher, around 137 ± 23 ng/100 ml and 213 ± 39 ng/100 ml respectively.

In these patients, treatment with dexamethasone significantly decreased the levels of testosterone and androstenedione to 22 ± 20 ng/100 ml (P<0.0005) and 43 ± 11 ng/100 ml (P<0.0005) respectively.

It can therefore be assumed that in orchiectomized patients these compounds are produced in the adrenal cortex, which in some cases is stimulated to produce a larger amount of strong androgens such as testosterone and weaker androgens such as androstenedione.

It has also been observed that those patients with an inadequate lowering of plasma testosterone levels after orchiectomy, did not show clinical improvement.

Further studies in a larger number of patients are needed in order to support this finding.

Herrada J, Hossan B, Amato R, et al:
Proc Am Soc Clin Oncol 13:237, 1994.

No abstract.

Scher HI, Kelly WK
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
J Clin Oncol 1993 Aug;11(8):1566-72

PURPOSE: To evaluate the effect of discontinuation of the antiandrogen, flutamide, in patients with metastatic prostate cancer who are progressing on hormonal therapy.

PATIENTS AND METHODS: Thirty-six patients with progressive disease on hormonal treatment that included flutamide had discontinuation of the antiandrogen. Thirty-five (95%) had progressive increases in prostate-specific antigen (PSA) levels, despite castrate levels of testosterone. Twenty-five patients (69%) were treated with combined androgen blockade (orchiectomy or gonadotropin-releasing hormone [GnRH] analog plus flutamide) as initial therapy and 11 (31%) were started on monotherapy alone. Patients who had not undergone a previous orchiectomy were continued on the GnRH analog. Patients were monitored clinically and with serial PSA measurements, radionuclide scans, and radiographs as indicated to assess response.

RESULTS: Considering the 35 patients with increasing PSA values, 10 (29%) showed a significant decline (> or = 80% in seven, and > or = 50% in three) in PSA from baseline. All 10 had received combined androgen blockade as initial therapy. The duration of decline was short (median, 5+ months; range, 2 to 10+), but was associated with improvement in clinical symptoms, while one patient had a partial response in an epidural mass with parallel decline in PSA. None of the patients started on single hormone therapies responded.

CONCLUSION: Discontinuation of flutamide was associated with a significant decrease in PSA values in 10 of 25 patients (40%; 95% confidence interval, 21% to 59%) and clinical improvement in a subset of patients who had an initial response, but later progressive disease on combined androgen blockade. A trial of flutamide withdrawal should be considered in patients progressing on total androgen blockade before the initiation of more toxic therapies. It is likely that flutamide withdrawal has contributed to the observed responses in phase II trials of both second-line hormonal therapies and new cytotoxic agents. Future phase II trials in hormone-refractory prostatic cancer must control for this observation, and insure that progression off flutamide is documented before initiation of alternative treatment.

Figg WD, Sartor O, Cooper MR, et al:
Pharmacology Branch, National Cancer Institute, Bethesda, Maryland, USA.
Am J Med 98:412-14, 1995.

No abstract.

Small EJ, Srinivas S
Department of Medicine, University of California, San Francisco, Mt Zion/UCSF Cancer Center 94115, USA.
Cancer 1995 Oct 15;76(8):1428-34

BACKGROUND. Flutamide withdrawal has been reported to be therapeutically efficacious for patients with hormone-refractory prostate cancer, with a reported prostate specific antigen (PSA) response rate of 29%.

METHODS. To evaluate the results of flutamide withdrawal in a large group of unselected patients, the medical records of 107 consecutive patients with metastatic prostate cancer who developed progressive disease while receiving flutamide therapy were reviewed retrospectively. Flutamide withdrawal was undertaken at the time of disease progression.

RESULTS. Eighty-two patients were evaluable. Of these, three had a > 80% fall in PSA value, and another nine had a > 50% decrease, for a response proportion of 14.6% (95% confidence interval 7.8%-24.2%). The median response duration was 3.5 months (range, 1-12+ months). Eight of patients treated with combined androgen blockade at the time of diagnosis of metastatic disease had a response (14%), whereas 4/25 responses (16%) were noted in patients in whom flutamide was added later, at the time of first progression. When patients who responded were compared with patients who did not respond, there was not a significant difference in age, pretreatment PSA level, type of gonadal androgen deprivation, or the likelihood of prior combined androgen blockade versus late addition of flutamide. The duration of prior therapy with flutamide was longer in patients who responded (21.5 vs. 12.0 months).

CONCLUSIONS. These findings confirm the flutamide withdrawal phenomenon in a large group of unselected patients, although its frequency is not as high as previously reported. In contrast to earlier reports, whether patients have had initial hormonal therapy with combined androgen blockade or monotherapy does not appear to be predictive of the likelihood of response to antiandrogen withdrawal.

Small EJ, Carroll PR
Department of Medicine, University of California, San Francisco.
Urology 1994 Mar;43(3):408-10

OBJECTIVE. To evaluate the relationship between antiandrogen withdrawal and change in prostate-specific antigen (PSA) when the antiandrogen in question is other than flutamide.

METHODS. Presented is a case of a patient in whom the antiandrogen casodex was discontinued after clinical progression despite combined androgen blockade.

RESULTS. A transient decline in serum PSA was observed after casodex withdrawal.

CONCLUSIONS. The relationship between antiandrogen withdrawal and a change in PSA may be a general phenomenon, not unique to flutamide.

Small EJ, Schelhammer P, Venner P, et al:
Proc Am Soc Clin Oncol 15:255A, 1996.

No abstract.

Dawson NA and McLeod DG
J Urol 153:1956-7, 1995.

No abstract.

Bissada NK, Kaczmarek AT
Department of Urology, Medical University of South Carolina, Charleston, USA.
J Urol 1995 Jun;153(6):1944-5

The phenomenon of regression of adenocarcinoma of the prostate after the withdrawal of antiandrogens is well documented. However, to our knowledge we report the first case of durable complete remission of hormone refractory prostate cancer after cessation of diethylstilbestrol. The drug was discontinued because the patient had disease progression while on diethylstilbestrol and withdrawal resulted in durable remission. In more than 3 years of followup since discontinuing diethylstilbes trol there has been no evidence of clinical or biochemical recurrence.

Culig Z, Hobisch A, Cronauer MV, Cato AC, Hittmair A, Radmayr C, Eberle J, Bartsch G, Klocker H
Department of Urology, University of Innsbruck, Austria.
Mol Endocrinol 1993 Dec;7(12):1541-50

Structural changes of the androgen receptor (AR) may contribute to the development of resistance to endocrine therapy in prostatic carcinoma. We have isolated AR cDNA fragments from seven tumor specimens derived from patients with advanced metastatic prostatic tumors. In one specimen obtained from a patient who failed to respond to endocrine and cytotoxic therapy we have detected a point mutation in the hormone-binding domain of the receptor. This AR mutation is a guanine-to-adenine transition at nucleotide 2671 that leads to substitution of methionine for the wild type valine at position 715. It is a somatic mutation because it was not present in the AR genomic DNA fragments isolated from prostatic and testicular tissues of the same patient. The mutant AR was recreated in an expression vector and transiently expressed in COS-7 and CV-1 cells. Hormone-binding assays revealed that the mutant receptor does not differ from the wild type receptor in its ability to bind androgen. The dissociation constant for the synthetic androgen mibolerone was 3 nM for both receptors. There was also no significant difference in binding of other steroids and nonsteroidal antiandrogens as revealed by competition binding assays. However, transfection experiments to determine the trans-activation potential of the mutant receptor produced differences in the action of this receptor compared to the wild type receptor. Dihydrotestosterone and the synthetic androgens methyltrienolone (R1881) and mibolerone were equally proficient in conferring trans-activation activity to both the mutant and wild type receptors. Adrenal androgens such as dehydroepiandrosterone and androstenedione, as well as progesterone mediated a higher trans-activation through the mutant than through the wild type receptor. These data demonstrate that the exchange of a single valine into methionine at position 715 in the AR promoters trans-activation not only by testicular but also by adrenal androgens and progesterone. This pattern of ligand-dependent trans-activation may have significance in the process controlling the progression of prostatic carcinoma.

Taplin ME, Bubley GJ, Shuster TD, Frantz ME, Spooner AE, Ogata GK, Keer HN, Balk SP
Department of Medicine, University of Massachusetts Medical Center, Worcester, USA.
N Engl J Med 1995 May 25;332(21):1393-8

BACKGROUND. Metastatic prostate cancer is a leading cause of cancer-related death in men. The rate of response to androgen ablation is high, but most patients relapse as a result of the outgrowth of androgen-independent tumor cells. The androgen receptor, which binds testosterone and stimulates the transcription of androgen-responsive genes, regulates the growth of prostate cells. We analyzed the androgen-receptor genes from samples of metastatic androgen-independent prostate cancers to determine whether mutations in the gene have a role in androgen independence.

METHODS. Complementary DNA was synthesized from metastatic prostate cancers in 10 patients with androgen-independent prostate cancer, and the expression of the androgen-receptor gene was estimated by amplification with the polymerase chain reaction. Exons B through H of the gene were cloned, and mutations were identified by DNA sequencing. The functional effects of the mutations were assessed in cells transfected with mutant genes.

RESULTS. All androgen-independent tumors expressed high levels of androgen-receptor gene transcripts, relative to the levels expressed by an androgen-independent prostate-cancer cell line (LNCaP). Point mutations in the androgen-receptor gene were identified in metastatic cells from 5 of the 10 patients examined. One mutation was in the same codon as the mutation found previously in the androgen-independent prostate-cancer cell line. The mutations were not detected in the primary tumors from of the two patients. Functional studies of two of the mutant androgen receptors demonstrated that they could be activated by progesterone and estrogen.

CONCLUSIONS. Most metastatic androgen-independent prostate cancers express high levels of androgen-receptor gene transcripts. Mutations in androgen-receptor genes are not uncommon and may provide a selective growth advantage after androgen ablation.

Fenton M-A, Shuster TD, Feris A, Taplin M-E, Kolvenbag G, Bubley GJ and Balk SP:
Clin Cancer Res 3:1383, 1997.

No abstract.

Olea N, Sakabe K, Soto AM, Sonnenschein C
Tufts University Health Science Schools, Department of Anatomy and Cellular Biology, Boston, Massachusetts 02111.
Endocrinology 1990 Mar;126(3):1457-63

The effect of steroidal and nonsteroidal "anti-androgens" on the proliferative capacity of androgen-sensitive LNCaP-FGC human prostate tumor cells in culture was studied using charcoal-dextran stripped human serum-supplemented media. Cyproterone and medroxyprogesterone acetates, flutamide, hydroxyflutamide, and anandron (R23908) were administered alone at concentrations between 3 X 10(-12) and 3 X 10(-6) M. Results indicated that although medroxyprogesterone induced maximal proliferation at 3 X 10(-9) M, the other "anti-androgens" (with the exception of flutamide that was ineffective) were effective at 3 X 10(-8) M and higher concentrations; the amplitude of the proliferative response by these compounds was comparable to that elicited by estradiol-17 beta (3 to 5-fold over control). None of the anti-androgens tested triggered the shutoff effect characteristic of androgen action. When 3 X 10(-10) M DHT and the above mentioned anti-androgens were administered simultaneously, a synergistic pattern was seen; on the contrary, 3 X 10(-8) M DHT cancelled the proliferative effect of each of the anti-androgens when administered simultaneously. The relative binding affinity of these anti-androgens to androgen receptors present in LNCaP-FGC cells did not correlate well with their proliferative efficiency. The data collected were interpreted within the premises of the negative control hypotheses for the regulation of cell proliferation in metazoans. Within those premises, results became compatible with the notion that first, "anti-androgens" elicited the proliferation of androgen-sensitive cells by neutralizing the effect of a serum-borne inhibitor (androcolyone-I); this event seems not to be mediated by androgens receptors. Second, anti-androgens did not trigger a proliferative shutoff response like androgens do, i.e. the proliferative pattern induced by anti-androgens was comparable to that elicited by estrogens and progestins. Third, when administered simultaneously with 3 X 10(-10) M DHT, anti-androgens behaved synergistically. Fourth, the DHT-induced shutoff effect consistently overrode the proliferative effect generated by anti-androgens and estrogens when added alone. Finally, taken together these results raise important questions regarding the therapeutic role of anti-androgens in prostate cancer.

Joyce R, Fenton MA, Rode P, Constantine M, Gaynes L, Kolvenbag G, DeWolf W, Balk S, Taplin ME, Bubley GJ
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
J Urol 1998 Jan;159(1):149-53

PURPOSE: A pilot study of the antiandrogen bicalutamide at 150 mg. a day for androgen independent prostate cancer was performed. This study was based on the possibility that androgen independent cases might display responses to additional hormonal agents.

MATERIALS AND METHODS: The study included 31 androgen independent cases with an increasing prostate specific antigen (PSA) and progressive disease. PSA measurements were used as the primary method of assessing response. However, PSA decline was also correlated with clinical status.

RESULTS: Seven patients demonstrated PSA declines of greater than 50% for 2 months or more, for an overall response rate of 22.5%. Responses were observed almost exclusively in patients treated with long-term flutamide as part of a complete androgen blockade regimen (43% response rate) in contrast to patients treated with androgen deprivation without flutamide (6% response rate). Of the 7 PSA responding patients bicalutamide resulted in a significant improvement in performance status and a decrease in analgesic requirement in 4 and 3 remained asymptomatic. Bicalutamide at 150 mg. a day was well tolerated, with the most frequent side effect being mild exacerbation of hot flashes.

CONCLUSIONS: Bicalutamide at this dose is modestly effective for some patients with androgen independent prostate cancer, particularly for those previously treated with long-term flutamide. This study indicates that previous antiandrogen therapy alters the response to subsequent hormonal agents.

Trachtenberg J, Halpern N, Pont A
J Urol 1983 Jul;130(1):152-3

Ketoconazole is an orally administered broad-spectrum antifungal agent that acts through the inhibition of the steroid synthetic pathways. At high doses in humans ketoconazole can lower rapidly serum testosterone and maintain it in the castrate range with frequent administration. This property suggested that ketoconazole might be useful in the treatment of prostatic cancer. We report a case of prostatic cancer in which ketoconazole resulted in rapid and sustained reduction in serum androgens as well as rapid induction of a clinical remission. Ketoconazole may be a valuable agent in the treatment of prostatic cancer.

Eichenberger T, Trachtenberg J, Chronis P, Keating A
Division of Urology, Toronto General Hospital, Ontario.
Clin Invest Med 1989 Dec;12(6):363-6

Ketoconazole has been recently used in the primary treatment of patients with metastatic cancer of the prostate and is identified as a potent inhibitor of cytochrome P450-dependent adrenal and testicular androgen production. The drug has also shown activity in patients failing conventional hormonal manipulation. We subsequently showed that ketoconazole in vitro has a direct cytotoxic effect on human androgen-independent prostatic cancer cell lines. In order to better define the possible role of ketoconazole on hormone-independent prostatic cancer, we incubated the cells from human androgen-independent prostatic cancer lines in a methylcellulose tumour colony assay with different doses of the drug and increasing doses of conventional cytotoxic agents (etoposide, bleomycin, vinblastine, methotrexate, and teniposide). We demonstrated synergistic suppression of prostate cancer clonogenic cell growth by ketoconazole in the presence of vinblastine or etoposide. This observation may assign a new and important role for ketoconazole as part of combination chemotherapy in the treatment of patients with advanced prostatic cancer.

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