Beyond tamoxifen new endpoints for breast cancer chemoprevention, new drugs for breast cancer prevention.
Although tamoxifen appears to markedly reduce breast cancer risk in women with a prior diagnosis of atypical hyperplasia or in situ carcinoma, it is not clear what other groups of women receive substantial benefit. Major breast chemoprevention priorities are to (1) develop new agents that (a) have fewer side effects, (b) are effective in ER--as well as tamoxifen-resistant precancerous tissue, and (c) are compatible with hormone therapy; and (2) develop efficient clinical strategies including prognostic and predictive morphologic and molecular biomarkers. Breast tissue may be repeatedly sampled for evidence of intraepithelial neoplasia by fine needle aspiration, ductal lavage, or needle biopsy to select candidates at highest short-term risk as well as to monitor response in small proof of principle studies prior to a large cancer incidence trial. Molecular marker expression may also be used to select a cohort most likely to respond to a particular agent. A large number of new agents are attractive as potential prevention agents and some are already in clinical prevention testing. Compounds which should be effective in ER + precancerous tissue but may have a better side-effect profile include new selective estrogen receptor modulators which lack uterine estrogen agonist activity, isoflavones, aromatase inactivators/inhibitors for postmenopausal women, and gonadotropin-releasing hormone regimens for premenopausal women. Retinoids, rexinoids, and deltanoids may be efficacious in ER+ tissue resistant to tamoxifen. Agents which should theoretically have activity in ER- or ER+ precancerous tissue include polyamine synthesis inhibitors, tyrosine kinase inhibitors, combined demethylating agents and histone deacetylase inhibitors, as well as metalloprotease and angiogenesis inhibitors. Sample Phase I and Phase II clinical trial designs are reviewed using modulation of molecular markers and breast intraepithelial neoplasia as the major endpoints.
Fabian
C J
CJ
University of Kansas Medical Center, Kansas City 66160-7320, USA. cfabian@kumc.edu
Kimler
B F
BF
D000782:Aneuploidy; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002278:Carcinoma in Situ / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017322:Clinical Trials, Phase II as Topic; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D018450:Disease Progression; D000518:Eflornithine / Q000627:therapeutic use; D023381:Endpoint Determination; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004967:Estrogens; D005260:Female; D017313:Fenretinide / Q000627:therapeutic use; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists; D006801:Humans; D006965:Hyperplasia; D007529:Isoflavones / Q000627:therapeutic use; D009363:Neoplasm Proteins / Q000032:analysis; D009376:Neoplasms, Hormone-Dependent / Q000517:prevention & control; D010641:Phenotype; D010880:Piperidines / Q000627:therapeutic use; D011073:Polyamines / Q000037:antagonists & inhibitors; D011230:Precancerous Conditions / Q000188:drug therapy; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011960:Receptors, Estrogen / Q000032:analysis; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use; D013629:Tamoxifen / Q000009:adverse effects / Q000627:therapeutic use; D013876:Thiophenes / Q000627:therapeutic use; D014594:Uterine Neoplasms / Q000139:chemically induced
D020533:Angiogenesis Inhibitors; D016588:Anticarcinogenic Agents; D047072:Aromatase Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D004967:Estrogens; D007529:Isoflavones; D009363:Neoplasm Proteins; D010880:Piperidines; D011073:Polyamines; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013876:Thiophenes; D013629:Tamoxifen; D017313:Fenretinide; D007987:Gonadotropin-Releasing Hormone; C115121:LY 353381; D011505:Protein-Tyrosine Kinases; D000518:Eflornithine