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Chappell, Julianne; Eckstein, Dan
doi: 10.1093/jnci/91.19.1599apmid: 10511579
September 30, 1999 (EMBARGOED FOR RELEASE 4 P.M. EDT October 5) Tamoxifen-Associated Endometrial Cancer Is Affected by Prior Hormone Use Women whose breast cancer was treated with tamoxifen have an increased risk for endometrial cancer, and the risk is highest for those women who had received estrogen replacement therapy or who are obese. These results are presented by Leslie Bernstein, Ph.D., University of Southern California School of Medicine, and colleagues, in the October 6 issue of the Journal of the National Cancer Institute . The authors used data on 324 case patients with endometrial cancer who had previously been treated for breast cancer. Control subjects—671 in number—were women with breast cancer who did not develop endometrial cancer and who were individually matched as closely as possible to the case subjects. The average age at breast cancer diagnosis was 65.9 years for case patients and 65.6 years for control subjects. The time interval between diagnosis of breast and endometrial cancers averaged 3.9 years. Data on breast cancer treatment and individual risk factors were collected for all participants through interviews and careful review of medical records. Tamoxifen was of particular interest because of its use in treating breast cancer and in preventing recurrence because its use was associated in some studies with increased risk of endometrial cancer and because tamoxifen is being proposed for use in breast cancer prevention for women at high risk of the disease. Overall, the authors report that tamoxifen therapy for breast cancer was associated with an increased risk of endometrial cancer with an odds ratio of 1.52 (that is, an increased risk of 52%). Women who had been on tamoxifen for more than 5 years had a fourfold greater chance of developing endometrial cancer. Prior use of estrogen increased the risk associated with tamoxifen use. Tamoxifen has proven benefits in extending the disease-free and overall survival of women being treated for breast cancer, and it reduces the risk of developing breast cancer in women at high risk for the disease. However, the authors conclude that tamoxifen therapy for breast cancer does increase the risk for endometrial cancer and that the risk is higher for women who have used estrogen replacement therapy. The authors conclude that such women may need closer surveillance for endometrial cancer when they are using tamoxifen. Contact: Brenda Maceo, University of Southern California (323) 442-2830; fax (323) 442-2832. Only One in Three Medicare Patients With Blood in Stool Samples Receives the Recommended Follow-up Testing About one third of the Medicare patients who tested positive for blood in their stool received the recommended follow-up testing, suggesting that population screening for colorectal cancer may be less effective and more costly than necessary. These results, from Jon Lurie, M.D., M.S., Veterans Affairs Medical Center, White River Junction, VT, and Gilbert Welch, M.D., M.P.H., will appear in the October 6 issue of the Journal of the National Cancer Institute. The fecal occult blood test (FOBT) has been shown to reduce mortality from colorectal cancer in controlled clinical trials, and Medicare now pays for such tests. The typical FOBT involves smearing a fecal sample onto cards after each of three bowel movements. The cards are then sent to a laboratory and tested for the presence of blood. Blood in the stool may be a sign of colorectal cancer. In their study, the authors identified 24,246 people aged 65 years or older who had FOBT under Medicare. These people had no indication of colorectal cancer before their tests. For every 1000 people tested, 93 appeared to have blood in their stool and received follow-up testing. However, only about one third of the people who tested positive received the recommended follow-up tests that are considered standard for detecting colorectal cancer—colonoscopy or flexible sigmoidoscopy and an air-contrast barium enema x-ray examination. Roughly one third received only partial colonic evaluation (flexible sigmoidoscopy only or barium enema only), and the remaining third were tested in a number of different ways, including an upper gastrointestinal series of x-rays, computed tomography, or magnetic resonance imaging of the abdomen, etc. Some individuals received a variety of tests. Of the 774 people who received a complete, recommended colon evaluation as a result of a positive FOBT, 241 had colonic polyps and 32 had colon cancer. The authors note that the screening FOBT offers little benefit without proper follow-up testing and treatment. Their data analysis indicates that, with current patterns of practice, population screening with the FOBT may be less effective than estimated from controlled trials. Furthermore, the use of multiple tests increases the costs of screening, costs that are not revealed in controlled clinical trials. Editorial writer John Bond, M.D., Veterans Affairs Medical Center and the University of Minnesota, Minneapolis, says screening the entire average-risk population for colorectal cancer would be very expensive. However, he notes, the cost of missing curable cancers or failing to prevent cancer by removing premalignant polyps may be even greater. A 1998 survey revealed that most people who had not been screened reported that no medical professional had ever recommended that they be screened, Bond says. A great deal of work remains in educating both the public and primary care physicians about the value of screening. Contact: Nancy Serrell (603) 646-2117; fax (603) 646-2850. Editorial: Linda Duffy (612) 725-2102; fax (612) 725-2049. Prostate-Specific Antigen May Retard Cancer Growth Prostate-specific antigen (PSA), widely tested for in men as an indicator of potential prostate cancer, may actually slow the growth of cancers through inhibition of blood vessel formation. These new results, which may explain the slow growth of prostate cancer and which call into question strategies to inhibit PSA expression as a cancer treatment, are presented by Anne Fortier, Ph.D., Barbara Nelson, Ph.D., Davida Grella, Ph.D., and John Holaday, Ph.D., of EntreMed, Inc., Rockville, MD, in the October 6 issue of the Journal of the National Cancer Institute. Despite its name, PSA is not specific to prostate cancer, having been found in breast, lung, and uterine cancers as well. In one study, women whose breast cancer tested positive for PSA had a better prognosis than patients whose tumors were negative. These and other findings led the authors to test the hypothesis that increasing PSA values may not reflect bad news about cancer progression. Rather, increasing PSA values may indicate that the body is fighting the cancer by producing its own proteins that inhibit the growth of new blood vessels, a process termed “ angiogenesis,” which the tumor must have if it is to flourish. To test the hypothesis that PSA may have antiangiogenic properties, the authors evaluated the effects of PSA on endothelial cell proliferation, migration, and invasion, three critical sequences in the orchestrated process of angiogenesis. The cells were stimulated with fibroblast growth factor or vascular endothelial growth factor, then treated with purified human PSA at concentrations ranging from 0.1 to 10μM . In these in vitro tests, PSA at concentrations of 0.3-5 μM significantly reduced endothelial cell functions. By contrast, PSA at these concentrations had no direct effect on prostate cancer cells or melanoma cells. In other tests, mice were inoculated with melanoma cells, then starting 3 days later some of the mice received injections of purified human PSA for 11 consecutive days. Compared with control mice that did not receive PSA, those treated with PSA showed a 40% reduction in the number of lung metastases. The authors note that their results suggest that PSA inhibits the growth of blood vessels associated with cancer progression. This may indicate that the elevation of PSA values in a variety of cancers is part of a normal process by which the body fights cancer progression. Therefore, they feel that their findings call into question various strategies to inhibit the expression of PSA in the treatment of prostate cancer and may indicate that PSA administration may be therapeutic in the treatment of a variety of cancers whose growth depends on angiogenesis. Contact: Mary Sundeen, EntreMed, Inc., (301) 738-2490; fax (301) 217-9594. Note: This memo to reporters is from the Journal staff and is not an official release of the National Cancer Institute (NCI) or Oxford University Press (OUP) nor does it reflect NCI or OUP policy. In addition, unless otherwise stated, all articles and items published in the Journal reflect the individual views of the authors and not necessarily the official points of view held by NCI, any other component of the U.S. government, OUP, or the organizations with which the authors are affiliated. Neither NCI nor any other component of the U.S. government nor OUP assumes any responsibility for the completeness of the articles or other items or the accuracy of the conclusions reached therein. Oxford University Press Oxford University Press
doi: jnci;91/19/1693apmid: N/A
Erratum: Tamoxifen for the Treatment and Prevention of Breast Cancer
doi: 10.1093/jnci/91.19.1693Apmid: N/A
Erratum: “Tamoxifen for the Treatment and Prevention of Breast Cancer,” Book Review by Mondzac [J Natl Cancer Inst 1999;91: 1505 (Issue 17)]. Text was inadvertently dropped from the fourth sentence of the second paragraph in column one. The first part of the sentence should read: “This section, which is entitled `How drugs are developed,' is written at an overly . . . .” In addition, PRR, Inc., the book's publisher, is located in New York state and not Minnesota. Finally, the previous edition of the book was published in 1996 and not “1 year ago.” The Journal regrets the errors. Oxford University Press
doi: 10.1093/jnci/91.19.1599pmid: N/A
Breast Cancer, Tamoxifen, and Endometrial Cancer Tamoxifen is used both to treat breast cancer and to reduce breast cancer incidence among high-risk women. Tamoxifen has estrogen-like effects in the uterus and is associated with increased risk of endometrial cancer. Bernstein et al. (p. 1654) examined whether other known risk factors for endometrial cancer would alter the tamoxifen-endometrial cancer relationship. They found that tamoxifen-associated risk increases with prior use of estrogen replacement therapy. Women who are both obese and have a history of estrogen replacement therapy have an even more pronounced risk of endometrial cancer when prescribed tamoxifen. Screening in the Elderly Screening with a fecal occult blood test (FOBT) has been shown to reduce colorectal cancer mortality in controlled trials and was recently approved for payment by Medicare. Using Medicare's National Claims History System, Lurie and Welch (p. 1641) identified 24,246 Americans over age 65 years who received FOBT as a routine screening test at a physician visit. The investigators observed that, in the subsequent 8 months, 9.3% (93/1000) tested positive and had relevant follow-up testing. Of those 9.3%, only a third had the test procedures recommended by the American College of Physicians. The researchers caution that, with this pattern of practice, widespread FOBT screening is likely to be more costly and less effective than estimated from controlled trials. In an editorial, Bond (p. 1602) points out that considerable educational effort is needed to educate the public about the impact of colorectal cancer and the value of screening. Primary care clinicians need to learn more about how to screen and follow-up abnormal results in their patients according to current guidelines, he says. These guidelines are intended to ensure that the clinical effectiveness of FOBT screening approximates the impressive efficacy of this method that has been demonstrated in scientific studies. Lung Resistance-Related Protein and Multidrug Resistance Lung resistance-related protein (LRP), the major vault protein in humans, is sometimes overexpressed in multidrug-resistant cells. (Vaults are cytoplasmic organelles composed of RNA and protein; approximately 5% of these structures are reported to associate with pore complexes in the nuclear membrane.) To determine whether LRP is directly involved in the expression of multidrug resistance, Kitazono et al. (p. 1647) inserted an LRP-specific ribozyme (an RNA that specifically cleaves the messenger RNA for LRP, thus inhibiting the synthesis of LRP) and studied its effect on multidrug resistance. They found that LRP is directly involved in multidrug resistance and has an important role in the transport of the cytotoxic drug Adriamycin from the nucleus to the cytoplasm. In an accompanying editorial, Dalton and Scheper (p. 1604) discuss the possible causal relationship between LRP expression and drug resistance and point out that, although currently there is no evidence that vaults actually transport or actually bind drugs, the results of Kitazono et al. are provocative and should stimulate additional research by other investigators using similar approaches. Prostate-Specific Antigen and Proliferation of Prostatic Stromal Cells Prostate-specific antigen (PSA) is a serine protease that can cleave insulin-like growth factor-binding protein-3 (IGFBP3) to decrease its affinity for insulin-like growth factor-I (IGF-I). Dissociation of the IGF-I-IGFBP3 complex renders IGF-I available to bind to its cell surface receptor and thus can stimulate cell proliferation. Sutkowski et al. (p. 1663) conducted studies to evaluate the potential for PSA to modulate the effects of IGF-I and IGFBP3 on the proliferation of human benign prostatic hyperplasia (BPH)-derived fibromuscular stromal cells in primary cultures. They observed a concentration-dependent proliferative response of BPH stromal cells to IGF-I and an inhibition of that response by IGFBP3. When stromal cells were incubated with PSA in the presence or absence of IGF-I and IGFBP3, a PSA-dependent increase in stromal cell numbers was evident. The investigators conclude that PSA can modulate the in vitro interactions between IGF-I and IGFBP3 and may play a role in the regulation of human prostatic fibromuscular cell growth. Mutations and Cervical Cancer Expression of human leukocyte antigen (HLA) class I molecules is frequently lost in cancers. Direct in vivo evidence for mutations in HLA class I genes has been lacking. In this issue, Koopman et al. (p. 1669) have used several polymerase chain reaction-based tests to identify HLA class I gene mutations in two cell lines derived from cervical carcinomas. They found that each cell line carried a different mutation in HLA class I genes that led to the loss of the relevant allelic expression and identified the same mutation in the corresponding parental tumor. These mutations may permit the tumor cells to escape from cytotoxic T cells that specifically kill cells expressing a certain type of HLA class I protein. Matrix Metalloproteinase Inhibitors Matrix metalloproteinases contribute to tumor invasion and metastasis. Several synthetic inhibitors of these proteins have been designed for clinical application to prevent metastasis. FasL, a transmembrane protein that induces apoptosis (programmed cell death), is cleaved by a metalloproteinase, thereby releasing soluble FasL and inhibiting apoptosis. Mitsiades et al. (p. 1678) tested whether matrix metalloproteinase inhibitors can lead to apoptosis in the Ewing's sarcoma family tumor cell lines by protecting the transmembrane FasL from cleavage by the metalloproteinases. They found that the metalloproteinase inhibitors caused accumulation of transmembrane FasL and induced apoptosis. Ewing's sarcoma cells treated with metalloproteinase inhibitors were sensitized to doxorubicin-induced apoptosis, suggesting a possible clinical use for metalloproteinase inhibitors in combination with standard apoptosis- inducing chemotherapy. Oxford University Press Oxford University Press
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