JNCI: Journal of the National Cancer Institute

Brown, Deborah L.;Cole, Bernard F.;Arrick, Bradley A.

doi: 10.1093/jnci/91.1.90apmid: 9890178

A number of multifactorial statistical models have been developed to estimate the chance that an individual carries a germline mutation in BRCA1 (1-3). These models are based principally on the cancer diagnoses in the family (particularly considering the type of cancer and age at diagnosis). We agree with Lakhani et al. (4) in their suggestion that histopathologic features of the breast cancers in a family could be used to increase the accuracy of predictions of the likelihood that a germline mutation in BRCA1 is involved. To this end, we note that perhaps the most distinctive and consistently reported features of breast cancers associated with BRCA1 mutations are the frequent absence of estrogen and progesterone receptors. Numerous investigators (5-7) have published reports comparing BRCA1 mutation-associated breast cancers with age-matched controls (e.g., either sporadic breast cancers or familial breast cancers lacking BRCA1 mutations), and all have reported statistically significant differences with regard to hormone receptor expression. Specifically, whereas only 25%-37% of the breast cancers not associated with BRCA1 mutation were estrogen receptor negative, 64%-92% of the cancers from BRCA1 mutation carriers were characterized as estrogen receptor negative (5-7). Progesterone receptor negativity was similarly a distinctive feature of BRCA1 mutation-associated breast cancers. Fewer data are available with regard to BRCA2 mutation-associated breast cancers. An illustration of the potential value of incorporating hormone receptor status into pedigree-based estimations of mutation status can be provided using Bayes' rule. For the purposes of these calculations, we will assume conservative estimates for estrogen receptor negativity rates of 33% for breast cancers not associated with BRCA1 mutation versus 67% for breast cancers in which BRCA1 mutation is involved. For a woman with an a priori risk of a germline BRCA1 mutation of 20%, conditioning on estrogen receptor positivity in her breast cancer would serve to cut her predicted risk of a BRCA1 mutation almost in half (to 11%), as outlined in Table 1. On the other hand, if her breast cancer were negative for this receptor, her adjusted risk of being a carrier for a BRCA1 mutation would increase to 34%. Estrogen receptor status could be even more helpful if this information were available for other affected family members as well. For example, for an affected woman whose a priori risk estimate is 10%-14% because she has an affected mother, conditioning on estrogen receptor data from both her mother's and her cancer could significantly refine the risk to as low as 3%-4% (if both cancers were receptor positive) or as high as 30%-40% (if both cancers were receptor negative). Note that these calculations apply only to the BRCA1 portion of heritable risk. While Lakhani et al. (4) suggest adjusting BRCA1 mutation risk estimates by using such tumor-associated features as mitotic count or proportion of the tumor perimeter occupied by continuous pushing margins, clear advantages of using hormone receptor status are that this information is a standard component of nearly all breast cancer pathology reports and that interobserver agreement of receptor status is high. In short, tumor hormone receptor expression may be a readily available, reliable, and powerfully predictive piece of information that could be of considerable use in estimating the likelihood of a BRCA1 germline mutation. Although Bayesian calculations such as described above could be applied to risk estimates derived from currently available regression models, this approach is theoretical and is based on some assumptions (e.g., that hormone receptor expression in breast cancer is not otherwise heritable). We would therefore urge those groups that develop multifactorial prediction models for BRCA1 mutation status to, if possible, incorporate tumor hormone receptor status into their models. Table 1. Example of Bayesian adjustment in the probability estimate of BRCA1 mutation status, conditioning upon tumor cell estrogen receptor (ER) expression* Probability   BRCA1 mutation   Present   Absent   A priori  0.20  0.80  Conditional  (ER positive)  0.33  0.67  Joint  0.066  0.536   Sum of joint probabilities =     0.066 + 0.536 = 0.602  Posterior  = 0.066/ 0.602 ≅ 0.11  = 0.536/ 0.602 ≅ 0.89  Probability   BRCA1 mutation   Present   Absent   A priori  0.20  0.80  Conditional  (ER positive)  0.33  0.67  Joint  0.066  0.536   Sum of joint probabilities =     0.066 + 0.536 = 0.602  Posterior  = 0.066/ 0.602 ≅ 0.11  = 0.536/ 0.602 ≅ 0.89  * This example is based on an a priori risk for a BRCA1 germline mutation of 20%, based on factors other than the person's breast tumor ER status (which in this example is positive). For this calculation, we assume ER positive-to-negative ratios of 1 : 2 and 2 : 1 in BRCA1 mutation-associated tumors and sporadic tumors, respectively. The joint probability is calculated by multiplying the a priori and the conditional probabilities, and the posterior probability is the joint probability divided by the sum of the joint probabilities. View Large References (1) Shattuck-Eidens D, Oliphant A, McClure M, McBride C, Gupte J, Rubano T, et al. BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. JAMA  1997; 278: 1242-50. Google Scholar (2) Parmigiani G, Berry D, Aguilar O. Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet  1998; 62: 145-58. Google Scholar (3) Frank TS, Manley SA, Olopade OI, Cummings S, Garber JE, Bernhardt B, et al. Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol  1998; 16: 2417-25. Google Scholar (4) Lakhani SR, Jacquemier J, Sloane JP, Gusterson BA, Anderson TJ, van de Vijver MJ, et al. Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst  1998; 90: 1138-45. Google Scholar (5) Johannsson OT, Idvall I, Anderson C, Borg A, Barkardottir RB, Egilsson V, et al. Tumour biological features of BRCA1-induced breast and ovarian cancer. Eur J Cancer  1997; 33: 362-71. Google Scholar (6) Loman N, Johannsson O, Bendahl PO, Borg A, Ferno M, Olsson H. Steroid receptors in hereditary breast carcinomas associated with BRCA1 or BRCA2 mutations or unknown susceptibility genes. Cancer  1998; 83: 310-9. Google Scholar (7) Verhoog LC, Brekelmans CT, Seynaeve C, van den Bosch LM, Dahmen G, van Geel AN, et al. Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet  1998; 351: 316-21. Google Scholar Oxford University Press

Brown, Deborah L.; Cole, Bernard F.; Arrick, Bradley A.

doi: N/Apmid: N/A

doi: 10.1093/jnci/91.1.19apmid: N/A

U.S. President Bill Clinton appointed six new members to the National Cancer Advisory Board for 6-year terms. Those named were: Elmer Huerta, M.D., a cancer prevention specialist at the Washington Hospital Center in the District of Columbia. He also hosts and produces health radio and cable television programs for Hispanic audiences. Susan M. Love, M.D., adjunct professor of surgery at the UCLA School of Medicine, Los Angeles and medical director of the Santa Barbara (Calif.) Cancer Institute. She is also a founder of the National Breast Cancer Coalition. James McGreevey, J.D., mayor of Woodbridge Township, N.J. and a candidate for governor of New Jersey in 1994. Arthur Nienhuis, M.D., director of the St. Jude Children's Research Hospital, Memphis, Tenn., a member of the St. Jude Department of Hematology-Oncology, and professor of pediatrics and medicine at the University of Tennessee School of Medicine, Memphis. Larry Norton, M.D., head of the Division of Solid Tumor Oncology at Memorial Sloan-Kettering Cancer Center, N.Y., and professor of medicine at Cornell University Medical School, New York. Amelie Ramirez, Dr.P.H., associate professor of medicine and associate director of the Center for Cancer Control Research at Baylor College of Medicine, Houston. She also is associate director for community research and co-program leader for the Cancer Prevention and Health Promotion Program at the San Antonio (Tex.) Cancer Center. She also is a member of the National Cancer Policy Board. Oxford University Press Oxford University Press

Dodds, Helen M.;Bishop, James F.;Rivory, Laurent P.

doi: 10.1093/jnci/91.1.91apmid: 9890180

Recently, Valencak et al. (1) reported an interesting observation relating to a cholinergic episode experienced by a patient receiving the combination of irinotecan and oxaliplatin in a phase II study. When irinotecan was given as a 1-hour infusion (80 mg/m2) at the end of the oxaliplatin 2-hour infusion (85 mg/m2), the patient had hypersalivation and abdominal pain. These symptoms resolved promptly with atropine and did not recur when irinotecan was administered alone 1 week later. Similarly, administration of the two drugs 1 day apart did not give rise to the same symptoms. However, rechallenge with the two drugs with the original protocol again led to cholinergic toxicity. These symptoms are typical of the acute syndrome experienced by some patients treated with irinotecan alone (2) and suggest that an interaction is occurring between the two drugs, with oxaliplatin potentiating the severity of irinotecan's cholinergic side effects. In response, Cvitkovic et al. (3) argued that this interaction is likely to be of little clinical significance because, in their hands at least, the irinotecan-oxaliplatin combination is safe and does not result in increased cholinergic toxicity. However, as Cvitkovic et al. pointed out, they administer atropine prophylactically to patients treated with this combination. Therefore, it is possible that the type of interaction reported by Valencak et al. (1) has been largely masked by atropine prophylaxis. The lack of an obvious pharmacokinetic interaction between the two drugs (4) would suggest that the toxicity is the result of pharmacodynamic factors. The cholinergic effects of irinotecan have been suggested to be mediated through ganglionic stimulation by the bipiperidino moiety released when irinotecan is activated to SN-38 by esterases. However, we have demonstrated that irinotecan is a potent direct inhibitor of human acetylcholinesterase at clinically relevant concentrations (5). Indeed, the potency and kinetics of inhibition of irinotecan are very similar to those of tacrine (Dodds HM, Ollis DL, Rivory LP: unpublished observations). The important features of this inhibition are that it is rapidly reversible and more pronounced for the lactone form of irinotecan. Potentiation of irinotecan's inhibition of acetylcholinesterase by oxaliplatin, although requiring formal demonstration, is supported indirectly by studies demonstrating that several other alkylating drugs used in oncology (e.g., cisplatin and cyclophosphamide) are moderate inhibitors of human acetylcholinesterase (6,7). Although these drugs are not known to yield symptoms consistent with cholinergic toxicity in clinical use, a possible mechanism for a pharmacodynamic interaction is nevertheless evident. Therefore, we agree with the conclusions of Valencak et al. (1) that this apparent interaction could be significant, particularly when atropine is not used prophylactically. Furthermore, the use of atropine in the development of other combinations containing irinotecan may mask similar occurrences of potentiated cholinergic toxicity, thereby preventing a complete characterization of their safety profiles. References (1) Valencak J, Raderer M, Kornek GV, Henja MH, Scheithauer W. Irinotecan-related cholinergic syndrome induced by coadministration of oxaliplatin [ letter]. J Natl Cancer Inst  1998; 90: 160. Google Scholar (2) Gandia D, Abigerges D, Armand JP, Chabot G, Da Costa L, De Forni M, et al. CPT-11-induced cholinergic effects in cancer patients [letter]. J Clin Oncol  1993; 11: 196-7. Google Scholar (3) Cvitkovic E, Marty M, Wasserman E, Cuvier C, Goldwasser F, Misset JL. Re: Irinotecan-related cholinergic syndrome induced by coadministration of oxaliplatin [letter]. J Natl Cancer Inst  1998; 90: 1016-7. Google Scholar (4) Lokiec F, Wasserman E, Santoni J, Mahjoubi M, Misset JL, Cvitkovic E. Pharmacokinetics (PK) of irinotecan/oxaliplatin (LOHP) combination: preliminary data of an ongoing phase I trial. Proc ASCO  1997; 16: A711. Google Scholar (5) Dodds HM, Rivory LP. The mechanism of the inhibition of aceylcholinesterase by irinotecan (CPT-11)—a lead in explaining the cholinergic toxicity of CPT-11 and its time-course. Proc Am Assoc Cancer Res  1998; 39: 327. Google Scholar (6) Kamal MA, Nasim FH, al-Jafari AA. Investigation of the effect of anti-neoplastic drugs, cyclophosphamide, cisplatin and methotrexate on the turnover kinetics of human erythrocyte acetylcholinesterase. Biochem Mol Biol Int  1996; 39: 293-302. Google Scholar (7) Kamal MA. Kinetics of human erythrocyte acetylcholinesterase inhibition by cis-diamminediaquaplatinum (II). Anticancer Res  1997; 17: 4487-91. Google Scholar Oxford University Press

Dodds, Helen M.; Bishop, James F. ; Rivory, Laurent P.

doi: N/Apmid: N/A

Chappell, Julianne; Eckstein, Dan

doi: 10.1093/jnci/91.1.1apmid: N/A

December 30, 1998 (EMBARGOED FOR RELEASE 4 P.M. EST January 5) Resistance of Breast Cancer to Tamoxifen Can Be Reversed in Animals by Antibodies to Transforming Growth Factor-β A new study may have identified and reversed a novel mechanism that makes some breast cancers resistant to the widely used drug tamoxifen. Carlos L. Arteaga, M.D., of the Vanderbilt University School of Medicine, and co-authors present their findings in the January 6 issue of the Journal of the National Cancer Institute. The authors knew from previous experiments that transforming growth factor-β (TGF-β ) is overproduced by some human breast cancers that are resistant to tamoxifen. Therefore, they determined in this study whether interfering with the production of TGF-β could reduce the resistance of certain human breast cancer cells to the effects of tamoxifen. Two human breast cancer cell lines were used in this study, one (LCC1) that produced low levels of TGF-β and responded to tamoxifen and another (LCC2) that overproduced TGF-β 2 and was resistant to tamoxifen. Both cell lines had high levels of estrogen receptors. The authors first measured in cell culture whether interference with TGF-β production in the LCC2 cells made them more responsive to the effects of tamoxifen and then in essence performed similar experiments on LCC1 and LCC2 tumors induced in two different types of mice. The authors report that the response of LCC2 cells to tamoxifen was not altered in cell culture by interfering with TGF-β secreted by the tumor cells. After LCC2 tumors were induced in nude mice, some of the mice were treated with tamoxifen alone, while others received tamoxifen and neutralizing TGF-β antibodies. Tamoxifen alone had no effect on tumor growth, while tumor growth was arrested in those receiving the combination. The same experiment with LCC2 cells, when repeated in beige mice, did not result in any slowing of tumor growth. LCC1 tumors were statistically significantly more sensitive to tamoxifen in nude mice as contrasted to beige mice. Since beige mice lack natural killer cell function, the authors propose that immune mechanisms may be involved partially in the antitumor effect of tamoxifen and that overproduction of TGF-β may interfere with this mechanism, thus contributing to tamoxifen resistance. Contact: Cynthia Manley, Vanderbilt University, (615) 322-4747; fax (615) 343-3890. Chromosome Used to Stop Growth of Breast Cancer Cells A specific human chromosome, when introduced into cells of human breast cancer growing in the laboratory, brought most of the cancer cells to a state of permanent growth arrest. This finding is presented by Andrew W. Cuthbert, Ph.D., of Brunel University, Uxbridge, United Kingdom, and colleagues, in the January 6 issue of the Journal of the National Cancer Institute. When most human cells divide, the ends of their chromosomes are often imperfectly replicated, and accumulation of these end defects, perhaps in combination with other processes, leads eventually to cell death. However, most cancer cells produce an enzyme called telomerase that compensates for the end defects in chromosome replication and thus promotes cell immortality. Interfering with cellular production of telomerase may be a way to stop the unchecked growth of cancer cells. The authors worked with cells of the human breast cancer cell line 21NT, cells that in laboratory culture grow immortally. Into these cancer cells they introduced by microcell transfer either human chromosome 3, 8, 12, or 20, obtained from normal cells. They then measured the subsequent telomerase activity in these hybrid cells, together with their growth potential. Those cell colonies containing introduced chromosomes 8, 12, and 20 showed an undiminished growth rate and normal telomerase activity when compared with unmodified control cultures. In marked contrast, colonies into which human chromosome 3 had been introduced showed, in most cases, complete growth arrest after 10-18 population doublings. Furthermore, telomerase activity was reduced by 98% or more in all of the colonies that entered growth arrest. Around one in 11 hybrid cell lines did not appear to respond to chromosome 3 and retained telomerase and immortality. The authors were able to detect overlapping deletions in the introduced chromosome 3 in these cells, enabling them to narrow the location of the gene or genes that turn off telomerase in normal breast tissue. The authors conclude that switching off telomerase in breast cancer cells allows them to regain the mechanism by which normal cells limit their growth. The search is now on for anti-cancer drugs that can produce the same effect. In an editorial, Jerry W. Shay, Ph.D., of The University of Texas Southwestern Medical Center, Dallas, notes that the study by Cuthbert et al. provides further confirmation of the importance of a telomerase inhibitor on chromosome 3 and that inhibition of telomerase could provide a novel approach to treating cancer. The challenge will be to find out how to make cancer cells age and stop dividing while our healthy cells continue to divide, he says. Contact: Professor Robert F. Newbold, Brunel University, United Kingdom, 44-1386-701176; e-mail [email protected]. Editorial: Heather Stieglitz, University of Texas, (214) 648-3404; fax (214) 648-9119. β-Carotene Supplementation Produces Precancerous Lung Lesions in Ferrets A new study has found that ferrets given β -carotene supplements developed precancerous changes in lung tissue, changes that were even more pronounced in ferrets that received the supplements and were also exposed to cigarette smoke. These findings are presented by Xiang-Dong Wang, M.D., Ph.D., Human Nutrition Research Center at Tufts University, Boston, and colleagues in the January 6 issue of the Journal of the National Cancer Institute. This work was prompted by a seeming contradiction, in that people who eat more fruits and vegetables have high levels of serum β -carotene and a lower risk of lung cancer, yet two studies using β -carotene supplements showed an increase in lung cancer among smokers and asbestos workers. Therefore, the authors studied the ferret, which absorbs and metabolizes β -carotene much as in humans and has also been used to study tobacco smoking and inhalation toxicology. Four groups of six ferrets each were divided as follows: controls, who received the unsupplemented diet that contained the equivalent in human terms of 2.3 mg per day of β -carotene; an unsupplemented group that was exposed to cigarette smoke daily for 6 months; a supplemented group that received the human equivalent of 30 mg per day of β -carotene; and a fourth group that was both supplemented with β -carotene and exposed to cigarette smoke. After 6 months, β -carotene concentrations were measured in the plasma and in lung tissues, and both cellular changes and changes in the expression of various genes were measured in lung tissues. Precancerous tissue changes were found in the lung tissues of β -carotene-supplemented animals, and this response was enhanced by exposure to tobacco smoke. Compared with the control group, all other animals had lower concentrations of retinoic acid (an active form of vitamin A that is protective against cancer) in lung tissue, which may be explained by alterations in certain gene expressions found in these tissues. The authors propose that smoking fosters breakdown products of supplemental β - carotene that differ from the breakdown products of carotenoid-rich natural diets and that these products of β -carotene metabolism can promote the formation of precancerous changes in lung tissue. Editorial writer Reuben Lotan, Ph.D., at The University of Texas M. D. Anderson Cancer Center, Houston, says that the work by Wang et al. provides a possible explanation for the enhancing effect of β -carotene supplementation on the development of lung cancer in smokers. However, he notes that there are several findings in the ferret study that are not characteristic of the response of human lungs to either tobacco smoke or β -carotene. For example, chronic smoking often leads to the development of squamous metaplasia in humans, but no such change was seen in the lungs of ferrets exposed to tobacco smoke only. Further, the end point of the ferret study was not cancer development. Therefore, extension of the ferret findings to development of human lung cancers in smokers supplemented with high-dose β -carotene must be done with caution. Contact: Gabriele Amersbach, Tufts University, (617) 636-0412; fax (617) 636-4075. Editorial, Michael Courtney (713) 792-0663; fax (713) 794-4418. 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: 10.1093/jnci/91.1.20apmid: N/A

Research!America will present March 9 the organization's third annual Advocacy Awards, given to individuals and organizations that have distinguished themselves as advocates for medical research. Former Sen. Mark Hatfield (R-Ore.) received the award for Lifetime Achievement as an advocate for medical research. Hatfield led the effort to create a National Fund for Health Research. Tenley Albright, M.D., a Boston surgeon and Olympic gold medalist in figure skating, received the award for Exceptional Contributions as a volunteer advocate for medical research. Katie Couric, anchor of NBC's Today show, received the award for Impact on Public Opinion through the media for her advocacy for colon cancer research, awareness, and prevention. Margaret E. Mahoney, an executive over time with the Robert Wood Johnson Foundation, the Carnegie Corporation, and the Commonwealth Fund, received the award for Sustained Leadership at the national level. The North Carolina Association for Biomedical Research won the organizational award for its work to provide information about medical advances and their impact on the state's economy. Iowa Names Weiner The University of Iowa Cancer Center, Iowa City, announced that George Weiner, M.D., associate professor of medicine at the university, was named director of the center. He has been interim director since Aug. 1. A university statement said that his appointment “underscores a commitment to bringing the best research and cancer care to the UI and the state of Iowa.” Oleksowicz Named at RPCI The Roswell Park Cancer Institute, Buffalo, N.Y., named Leslie Oleksowicz, M.D., associate professor of medicine and director of its Genitourinary Solid Tumor Program. She had been on the faculty of both the Albert Einstein College of Medicine and the Mount Sinai Medical Center, New York. The announcement said that Oleksowics will work with colleagues at RPCI to develop a translational program for genitourinary tumors. Foundation Appoints Penn The Cure For Lymphoma Foundation, New York, named Ilene Penn as associate executive director. She will serve as public policy analyst, counsel, outreach coordinator, and administrator. Penn has been a senior associate with Podesta Associates, a public policy firm in Washington, D.C. Yeh to CytoMed CytoMed, Inc., Cambridge, Mass., named C. Grace Yeh, Ph.D., to the newly created position of chief scientific officer. She will continue to hold her previous position — vice president for product development — as well. CytoMed is a biopharmaceutical company that develops products for the treatment of inflammatory diseases. Scholars Program Created The National Cancer Institute announced that it established the NCI Scholars Program to provide outstanding new investigators the opportunity to develop their first independent research program within the institute's intramural environment and to facilitate the investigators' successful transition to an environment outside of NCI. Individuals selected will be provided with facilities, budget, salary, and personnel for up to 4 years, and will be eligible for salary and research support for up to 2 years at an extramural institution through a non-competing Career Transition Award. Further information is available from the NCI Cancer Training Branch, whose phone is 301-496-8580. The fax number is 301-402-4472. Clinical Trials Covered United HealthCare Corp., announced that in January it is beginning to pay for cancer clinical trials for eligible members through a Clinical Trials Pilot Program developed by an agreement between the company and the Coalition of National Cancer Cooperative Groups. In the pilot program, United will pay for a member's care through any multi-institutional trial sponsored by the Coalition or by any one of the cooperative groups that make up the Coalition. AACR Call for Proposals The American Association for Cancer Research issued a call for proposals for its research fellowship and for its career development awards. The deadline for receipt of applications for both is Jan. 15. Awardees will be selected by March and the first payments will be made in July. Information is available from AACR at 215-440-9300. The fax number is 215-440-9372, and the e-mail address is [email protected]. In addition, application forms can be downloaded from the AACR website (www.aacr.org). Open in new tabDownload slide Sen. Mark Hatfield Open in new tabDownload slide Dr. C. Grace Yeh Oxford University Press Oxford University Press

doi: 10.1093/jnci/91.1.1pmid: N/A

Tamoxifen Resistance and Transforming Growth Factor-β Breast cancers can become resistant to treatment with the drug tamoxifen. Arteaga et al. (p. 46) have performed studies to uncover mechanisms that may play a role in this resistance. By use of a tamoxifen-resistant human breast cancer cell line, LCC2, and a related tamoxifen-sensitive line, LCC1, they showed that large amounts of transforming growth factor-β2 were secreted by the resistant line but not by the sensitive line. They also showed that the growth of LCC2 tumors in nude mice could be inhibited by treatment with tamoxifen and neutralizing antibodies against transforming growth factor-β. Similar treatment did not inhibit LCC2 tumor growth in beige/nude mice, which are deficient in natural killer cell function. These data suggest that the antitumor effects of tamoxifen may be mediated, in part, by natural killer cell function and that, by abrogating this mechanism, transforming growth factor-β2 may contribute to tamoxifen resistance. Telomerase: Cellular Immortality and Its Reversal Telomerase, the enzyme responsible for maintaining the length of telomeres (the ends of chromosomes) during DNA replication, is repressed in normal cells, leading to a progressive shortening of telomeres and the arrest of cell growth. In cancerous cells, the telomerase is active, facilitating telomere maintenance and allowing continuous cell growth. Cuthbert et al. (p. 37) investigated whether specific chromosomal DNA sequences are responsible for repressing telomerase in normal cells and are either defective or absent in cancer cells. They found that chromosome 3 (in contrast to chromosome 8, 12, or 20) of normal human cells, when experimentally introduced into cancer cells, can repress telomerase activity and induce growth arrest. This shows that specific telomerase repressor sequences present on normal chromosome 3 are not functional in cancer cells. In addition, the authors have identified, by detailed gene mapping, two regions on the short arm of chromosome 3 where telomerase regulator genes may be located. In an editorial, Shay (p. 4) notes the importance of identifying genes in the telomerase repression pathway and discusses the prospects of treating cancer by inhibiting telomerase. After treatment with conventional regimens, anti-telomerase agents may be used to limit the proliferative capacity of surviving cancer cells and prevent recurrence. He suggests that use of telomerase inhibitors along with other cancer therapeutic agents may more effectively achieve complete cancer remissions. Ferrets, β-Carotene, and Tobacco Smoke Recent intervention studies have demonstrated an increase in the risk of lung cancer among smokers taking high doses of β-carotene—an unexpected result given epidemiologic studies that show a lower risk of cancer, especially lung cancer, among individuals who eat more fruits and vegetables, which are rich in β-carotene. Wang et al. (p. 60) have used ferrets, which absorb and metabolize β-carotene similarly to humans, to determine the molecular effects of β-carotene in the presence and absence of tobacco smoke. The authors report that expression of retinoic acid receptor β is suppressed and that activator protein-1 is overexpressed in the lung tissue of animals receiving high doses of β-carotene and exposed to tobacco smoke. These molecular alterations could lead to diminished retinoid signaling and accelerated cell proliferation, possibly enhancing lung tumor formation. In an editorial, Lotan (p. 7) discusses the results of Wang et al., including their explanation for the enhancing effect of β-carotene supplementation on lung cancer in smokers. He points out the ways in which the response to ferrets exposed to smoke, the animal model used, is similar to and different from the response of humans exposed to smoke, especially with regard to squamous metaplasia. He suggests caution when extrapolating the findings from the ferret to human lung carcinogenesis. Vinorelbine, Quality of Life, and Advanced Non-Small-Cell Lung Cancer There are few chemotherapeutic options available for patients with advanced non-small-cell lung cancer, especially for those, such as elderly patients, who may not to be able to tolerate potential toxic effects. Vinorelbine is a drug that is well tolerated by elderly patients with this form of cancer. The Elderly Lung Cancer Vinorelbine Italian Study (ELVIS) Group (p. 66) reports that vinorelbine treatment improves the survival of elderly patients with advanced disease and possibly improves their overall quality of life. Breast Cancer and Marital Stability The belief that husbands desert their wives who have breast cancer is not uncommon but has been based to a large extent on anecdotal evidence found in popular women's magazines. In a study of women from Quebec City and its surrounding regions, Dorval et al. (p. 54) have compared the frequency of marital breakdown among women who had breast cancer with that among control women. They found that marital breakdown was never higher in women with breast cancer than in control women, and they conclude that breast cancer does not appear to be associated with marital breakdown among Quebec women. Predicting Sarcoma Aggressiveness Several types of sarcomas—cancers primarily of connective tissue origin—are characterized by aberrations of human chromosome 9. Orlow et al. (p. 73) investigated whether there was an association between alterations (deletions and rearrangements) in certain genes related to the control of cell growth that map to chromosome 9 and the aggressiveness of the sarcoma. In a study of sarcomas from 46 patients, the researchers characterized the status of the neighboring INK4A and INK4B genes in cells from the patient's sarcoma, as well as the status of known tumor suppressor genes and oncogenes. They were particularly interested in changes in INK4A, a gene unusual in that it encodes two distinct proteins, p16 and p19ARF (for alternate reading frame). Orlow et al. found a statistically significant association between alterations in INK4A and INK4B and poor survival of the patient. The researchers suggest that these gene alterations may provide clues to the prognosis and proper treatment of patients with sarcomas. Oxford University Press Oxford University Press

Shay, Jerry W.

doi: N/Apmid: N/A

Shay, Jerry W.

doi: 10.1093/jnci/91.1.4pmid: 9890161