Method of identifying and treating invasive carcinomas

Details Method of identifying and treating invasive carcinomas Method of identifying and treating invasive carcinomas

2003-02-18

2004-02-10

Housel, James (Department: 1648)

Chemistry: analytical and immunological testing

Cancer

C424S009100, C435S007100, C435S007230

Reexamination Certificate

active

06689614

ABSTRACT:

BACKGROUND AND PRIOR ART
For men in the U.S., prostate cancer is the most commonly diagnosed cancer, and the second leading cause of cancer-related death (Greenlee R T, Murray T. Bolden S. Wingo P A. Cancer statistics, 1999. Ca: a Cancer Journal for Clinicians 2000:50:7-33). Prostate cancers originate as localized lesions; some of these localized lesions will progress to become invasive, migratory and metastatic. Our current understanding of the mechanisms of the prostate cancer invasion process, however, is poor. Our ability to predict the acquisition of invasive potentials by a prostate cancer is limited.
The mechanisms leading to the development of a prostate cancer are complex. Currently, it is believed to be the result of multiple transformation steps from normal prostate glandular cells (Carter H B. Piantadosi S. Isaacs J T. Clinical evidence for and implications of the multistep development of prostate cancer. Journal of Urology. 143(4):742-6, 1990). The initial steps result in what are described as prostatic interepithelial neoplastic (PIN) lesions (Isaacs J T. Molecular markers for prostate cancer metastasis. Developing diagnostic methods for predicting the aggressiveness of prostate cancer. [Review] [92 refs] American Journal of Pathology. 150(5):1511-21, 1997). These PIN lesions may then typically have three different fates based on an assessment of their impact to the patient. The PIN lesions can remain as such, not producing histologically detectable prostate cancer, or further transform into histologically detectable prostate cancer. Most of the histologically detectable prostate cancers will be asymptomatic in the patient and remain non-manifest clinically as many are discovered post-mortem (Carter H Coffey D. Prostate Cancer: the magnitude of the problem in the United States. In a Multidisciplinary Analysis of Controversies in the Management of Prostate Cancer. (Eds. Coffey D. Resnick M. Door R. et al.), pp1-9, Plenum Press, 1988; Carter H B Piantadosi S. Issacs J T. Clinical evidence for implications of the multistep development of prostate cancer. Journal of Urology. 143(4):742-6, 1990; Scardino P T. Weaver R. Hudson M A. Early detection of prostate cancer. [Review] [102 refs] Human Pathology. 23(3):211-22, 1999). Prostate cancers are diagnosed clinically by an estimate of size and location using the TNM staging system (Denis L J. Staging and prognosis of prostate cancer. European Urology. 24 Suppl 2:13-8, 1993), and by pathological staging based on an examination of the histology of the removed prostate via either biopsy or prostatectomy using a system by D. F. Gleason, (Gleason D F. Classification of prostatic carcinomas. Cancer Chemotherapy Reports-Part 1. 50(3):125-8, 1966). About 50% of prostate cancer cases receiving treatment are diagnosed clinically as advanced, or, non-organ-confined (Scardino P T. Weaver R. Hudson M A. Early detection of prostate cancer. [Review] [102 refs] Human Pathology. 23(3):211-22, 1992), for which no effective treatment exists (Yagoda A. Petrylak D. Cytotoxic chemotherapy for advanced hormone-resistant prostate cancer. [Review] [63 refs] Cancer. 71(3 Suppl): 1098-109, 1993 and Petrylak, 1993). Of the remaining 50% cases, ⅓ (~50,000) are diagnosed as organ-confined but micrometastasis may be present. The final group of patients (~100,000) have truly organ-confined prostate cancer and can be cured by radical prostatectomy (Sgrignoli A R Walsh P C. Steinberg G D. Steiner M S. Epstein J I. Prognostic factors in men with stage D1 prostate cancer: identification of patients less likely to have prolonged survival after radical prostatectomy [see comments]. Journal of Urology. 152(4):1077-81, 1994; Zincke H. Oesterling J E. Blute M L. Bergstralh E J. Myers R P. Barrett D M. long term (15 years) results after radical prostatectomy for clinically localized (stage T2c or lower) prostate cancer [see comments]. Journal of Urology. 152(5 Pt 2): 1850-7, 1994) or left untreated (watchful waiting) without the risk of life-threatening or life-altering. For the patients with non-organ-confined prostate cancers (discovered via either biopsy or surgery), undergoing systemic treatment early is essential to the management of their cancer (Yagoda A. Petrylak D. Cytotixic chemotherapy for advanced hormone-resistant prostate cancer [Review] [63 refs] Cancer. 71(3 Suppl): 1098-109, 1993). Consequently, it will be ideal, both medically and economically, if one could precisely predict upon early pathological examination of the tumor, which group of patients will have truly organ-confined disease versus which group will have invasive prostate cancer.
Clinical staging of prostate cancer generally depends on the results of three tests that are performed in the following order: a PSA (prostate-specific antigen) blood test as a screening method; DRE (digital rectal examination) for an initial indication of palpable disease; and, a biopsy to obtain samples for histological examination. Prostate cancers, removed either via biopsy or surgery, are graded histologically by the system of Gleason. (Gleason D F. Classification of prostatic carcinomas. Cancer Chemotherapy Reports—Part 1. 50(3):125-8, 1966), which is an evaluation of how aggressive and how poorly-differentiated the prostate cancers are. The aggressiveness of prostate tumors: of low Gleason scores (<5) is limited; of high Gleason scores (8-10) are highly aggressive; but, for the intermediate Gleason-score (5-7) prostate cancers (76% of prostate tumors), the accuracy of predicting their aggressiveness is poor (Gleason D F. Mellinger G T. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. Journal of Urology. 111(1):58-64, 1974). Thus, the ability to accurately determine the aggressiveness of these intermediate Gleason-score prostate tumors has remained as a practical challenge to, and a primary goal for, prostate cancer research (Isaacs J T. Molecular markers for prostate cancer metastasis. Developing diagnostic methods for predicting the aggressiveness of prostate cancer. [Review] [92 refs] American Journal of Pathology. 150(5):1511-21, 1997). Especially with regard to the number of patients (150,000) facing a decision of whether to undergo systemic treatment, the most urgent demand in prostate cancer care is the development of methods to enhance our ability to accurately predict the aggressiveness of the tumors with Gleason scores of 5-7.
It is now commonly believed that cancers occur via multiple transformation steps by accumulating mutations in three classes of genes: proto-oncogenes (Park M. Oncogenes. In The Genetic Basis of Human Cancer (Eds. Vogelstein B and Kinzler K W). pp205-28. McGraw-Hill Health Professions Divisions, 1998); tumor-suppressor genes (Knuutila S. Aalto Y. Bjorkqvist A M. EL-Rifai W. Hemmer S. Huhta T. Kettunen E. Kiuru-Kuhlefelt S. Larramendy M L. Lushnikova T. Monni O. Pere H. Tapper J. Tarkkanen M. Varis A. Wasenius V M. Wolf M. Zhu Y. DNA copy number losses in human neoplasms. [Review] [197 refs] American Journal of Pathology. 155(3):683-94, 1999); and, DNA repair genes (Knuutila S. Aslto Y. Bjorkqvit A M. EL-Rifai W. Hemmer S. Huhta T. Kettunen E. Kiuru-Kuhlefelt S. Larramedy M L. Lushnikova T. Monni O. Pere H. Tapper J. Tarkkanen M. Varis A. Wasenius V M. Wolf M. Zhu Y. DNA copy number losses in human neoplasms. [Review] [197 refs] American Journal of Pathology. 155(3):683-94, 1999). The histological prostate cancers for which the prediction of clinical aggressiveness is difficult (those with the intermediate Gleason scores 5-7) probably have not gone through the necessary “multi-step” transformation to acquire the potentials to behave aggressively (as would the high-grade cancers). This notion was supported by studies comparing the course of prostate cancer development among men in Japan and in the U.S., and Japanese men who migr

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