Susumu Akimoto

Codon 877 mutation in the androgen receptor gene in advanced prostate cancer : Relation to antiandrogen withdrawal syndrome

The growth of prostate cancer is androgen responsive, and androgen receptor (AR) is thought to play an important role in the development of this cancer. Recently, some reports demonstrated that AR gene mutations were detected in human prostate cancer tissues. We have previously reported that one of eight endocrine therapy‐resistant prostate cancer cases showed AR gene mutation [Suzuki] et al: J Steroid Biochem Mol Biol46:759‐76, 19931. To further investigate structural abnormality of the AR in a large number of human prostate cancers, exons E H encoding DNA‐ and hormone‐binding domains were examined by single‐strand conformation polymorphism analysis of polymerase chain reaction products and direct sequencing. Tissues surgically removed from 30 cases of stage B or C prostate cancer and from 22 cases of endocrine therapy‐resistant cancers obtained at autopsy were used in the study. Three out of 22 cancer death cases (14%) revealed AR gene mutations, one of which contained two different mutations‐exon D in cancerous prostate and exon H in metastatic tissues. In the other two cases, AR gene mutations in exon H were found in metastatic tissues. All three cases in metastatic tissues showed the same mutation at codon 877 (877Thr + Ala). In stage B or C cancer tissues and the other cancer death samples, no AR mutation was detected. The mutation in exon H was identical to that reported in a human prostate cancer cell line, LNCaP. These results indicate that AR gene mutation scarcely occurs in the early stage of prostate cancer and that the mutation is found in relation to endocrine therapy resistance. Two patients with an AR gene mutation at codon 877 revealed a remarkable fall in prostate‐specific antigen after withdrawal of antiandrogen. Data on the other case were not available. These results indicate that a codon 877 mutation in the AR gene in advanced prostate cancer evokes the antiandrogen withdrawal syndrome. To our knowledge, this report is the first description of relationship between an AR mutation at codon 877 and the antiandrogen withdrawal syndrome.

Long-term results of a randomized trial for the treatment of stages B2 and C prostate cancer: radical prostatectomy versus external beam radiation therapy with a common endocrine therapy in both modalities

OBJECTIVES To improve the treatment of locally advanced prostate cancer (Stages B2 and C), a prospective randomized trial was conducted to compare radical prostatectomy versus external beam radiotherapy with the combination of endocrine therapy in both modalities. METHODS One hundred patients were enrolled and 95 were evaluated. Forty-six patients underwent radical prostatectomy with pelvic lymph node dissection, and 49 were treated with radiation by linear accelerator with 40 to 50 Gy to the whole pelvis and a 20-Gy boost to the prostatic area. For all patients, endocrine therapy was initiated 8 weeks before surgery or radiation, and continued thereafter. The living patients were asked to respond to a quality-of-life questionnaire. RESULTS The follow-up period ranged from 6.0 to 94.4 months (median 58.5). The progression-free and cause-specific survival rates at 5 years were 90.5% and 96.6% in the surgery group and 81.2% and 84.6% in the radiation group, respectively. The surgery group had better progression-free and cause-specific survival rates (P = 0.044 and 0.024, respectively). More patients in the surgery group complained of urinary incontinence. The questionnaire revealed that quality of life was less disturbed in the radiation group. CONCLUSIONS Radical prostatectomy combined with endocrine therapy may contribute to the survival benefit of patients with locally advanced prostate cancer. External beam radiotherapy in combination with endocrine therapy can be used in selected patients because of its low morbidity.

Microsatellite Instability and Other Molecular Abnormalities in Human Prostate Cancer

Microsatellites are highly polymorphic, short‐tandem repeat sequences dispersed throughout the genome. Instability of these repeat sequences at multiple genetic loci may result from mismatch repair errors, and occurs in hereditary nonpolyposis colorectal carcinoma and certain sporadic cancers. To examine microsatellite instability during the pathogenesis of human prostate cancer, we screened 48 prostate cancer cases (20 stage B, 10 stage C and 18 endocrine therapy‐resistant cancer‐death cases) for replication error at 17 microsatellite marker loci on 9 chromosomes. Microsatellite instabilities were found in 7 of 48 cases (14.6%), and all 7 cases showing the instability were poorly differentiated adenocarcinomas. Moreover, microsatellite instabilities were more frequently observed in cancer‐death cases (6/18, 33%) than in stage B+C cases (1/30, 3.3%). These data suggest that micro‐satellite instability is an important genetic change related to the progression of a subset of human prostate cancer cases. It is suggested to be associated with extensive, concurrent molecular changes including androgen receptor gene mutations, as well as frequent loss of heterozygosity at chromosomal regions 8p, 10q, and 16q.

State of Adenomatous Polyposis Coli Gene and ras Oncogenes in Japanese Prostate Cancer

Genetic alterations of ras oncogenes (K‐, H‐ and N‐ras) and adenomatous polyposis coli (APC) gene in tissues of prostate cancer from Japanese patients were examined using PCR‐SSCP (polymerase chain reaction‐single strand conformation polymorphism) analysis and direct sequencing. Tissues from 8 cases of untreated stage B prostate cancer surgically removed and from 10 cases of endocrine therapy‐resistant metastatic disease obtained at autopsy were used in the present study. In four out of 18 cases (22%), ras point mutations were found, two in either codon 12 or 61 of K‐ras and two in either 13 or 61 of H‐ras. These point mutations were detected in one of the stage B cases (13%) and in three of the autopsy cases (30%). All these cases were poorly differentiated adenocarcinoma. In autopsy cases showing ras mutation in cancerous prostate, the same alteration was observed in metastatic tissues. No APC gene mutation was detected in any sample, although polymorphism was found in some cases. These results indicate that ras oncogene mutations are related to the progression of prostate cancer, whereas APC gene alteration is not involved in tumorigenesis and development of this cancer.

Antiandrogen withdrawal syndrome in prostate cancer after treatment with steroidal antiandrogen chlormadinone acetate

OBJECTIVES A case report is presented of 2 patients whose levels of serum prostate-specific antigen (PSA) improved after the withdrawal of a steroidal antiandrogen. METHODS Two cases with prostate cancer had been treated with surgical castration and the steroidal antiandrogen chlormadinone acetate (CMA), and, on disease progression, the administration of CMA was terminated. RESULTS Following withdrawal of CMA, a fall in PSA levels and remarkable clinical improvement were observed in both cases. One patient revealed a decrease and the other an increase in serum prostate acid phosphatase after the discontinuation of CMA. Serum levels of testosterone, prolactin, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione were not significantly elevated after CMA withdrawal. CONCLUSIONS Withdrawal of the steroidal antiandrogen CMA resulted in a decline in PSA levels and clinical improvement in prostate cancer patients with disease progression. Changes in testosterone, prolactin, or adrenal androgens were not a cause of the antiandrogen withdrawal syndrome.

Tumor marker doubling time in patients with prostate cancer : determination of prostate-specific antigen and prostatic acid phosphatase doubling time

To estimate the growth rate of prostate cancer, the doubling times of prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) were determined in 51 patients: 44 were refractory to endocrine therapy, and 7 were in an untreated state. Since an exponential increase in PSA and PAP was observed in all patients, the doubling time was calculated from a semilogarithmic plot of the respective markers. PSA doubling time was almost identical with that of PAP. The tumor marker doubling time in untreated patients was approximately 10 times greater than that in the patients who were refractory to endocrine therapy. In endocrine refractory patients, the tumor marker doubling time in patients who showed deterioration of bone lesions was less than that in patients with local regrowth and/or lymph node metastasis. The prognosis of endocrine refractory patients from the time showing tumor marker failure was examined. The group showing the longest time (> 80 days) had better prognosis than that shown by the other groups with shorter doubling times. It is concluded that the determination of tumor marker doubling time is of value for measuring the growth rates of prostate cancer, and for assessing prognosis after relapse.

Smoking and Obesity in Relation to the Etiology and Disease Progression of Prostate Cancer in Japan

Background:

Histochemical examination of expression of ras p21 protein and R 1881-binding protein in human prostatic cancers.

Expression of ras p21 was examined with monoclonal antibody RASK-3 in normal, benign hyperplasic, and cancerous prostates. In patients with stage D2 disease who received endocrine therapy, the relation between ras p21 expression, response to therapy, and prognosis was studied. In these patients, R 1881-binding protein (androgen receptor and progestin-binding protein) was also examined. Non-cancerous cells and most cancer cells from stage A patients did not express ras p21, while expression increased with both higher staging and grading. Staging pelvic lymphadenectomy was done in some stage A2-C cases, and presence of nodal metastasis was correlated with ras p21 expressions in the primary tumours. In stage D2, there was no correlation between ras p21 expression and R 1881-binding protein. Response to therapy and survival did not correlate with expression of ras p21, but was influenced by presence of R 1881-binding protein.

Clinical Course of Bone Metastasis from Prostatic Cancer Following Endocrine Therapy: Examination with Bone X-Ray

X-ray findings of bone metastatic lesions from 81 cases of stage D2 prostatic cancer were examined before and following endocrine therapy. Untreated lesions were classified into five types; osteoblastic (15%), mixed, but mainly osteoblastic (31%), mixed, but mainly osteolytic (17%), osteolytic (10%), and undetermined with a positive bone scan (27%). Patients with two mixed types had a tendency of widely speeded areas of metastasis and elevated serum prostatic acid phosphatase. Temporal enlargement of sclerotic lesion immediately after the start of therapy did not indicate disease progression. In many cases, changes from osteolytic to osteoblastic patterns were noticed in the same lesion regardless of the effects of endocrine therapy. Remodeling to the sclerotic pattern appeared as curative changes. From these findings, it was concluded that the natural course of bone lesions showed a tendency to change from the osteolytic to osteoblastic type and relapse was often accompanied by an increase of the osteolytic type lesion. Evaluation of therapeutic effects based on remodeling, changes in number and areas of lesions, and the appearance of new lesion correlated well with prognosis.

Pattern of progression and survival in hormonally treated metastatic prostate cancer

Background: Patients with prostate cancer generally respond to androgen ablation therapy, but progression to androgen‐independence is frequently observed. To further evaluate disease progression, the pattern of progression and survival in hormonally treated metastatic prostate cancer was examined.