"JNCI: Journal of the National Cancer Institute"

Arnold, Katherine; Eckstein, Dan

doi: 10.1093/jnci/92.18.1455-apmid: N/A

September 14, 2000 (EMBARGOED FOR RELEASE 4 P.M. EDT September 19) Results from a major Canadian study show that yearly mammograms combined with physical breast examination for women 50–59 years old — who were also trained to perform breast self-examination — does not lower breast cancer mortality compared with yearly physical examination alone. Dr. Anthony Miller of the University of Toronto and colleagues, reporting for the Canadian National Breast Screening Study-2, present their results in the September 20 issue of the Journal of the National Cancer Institute. They note that mammography in combination with physical breast examination detected more lymph-node negative and more small breast cancers than physical examination alone. However, after 13 years of follow-up, breast cancer deaths were practically identical in the two groups. The study involved 15 screening centers in six Canadian provinces. From January 1980 through March 1985, study entrants were randomly assigned to one of the two arms of the study—19,711 women to the arm receiving mammograms and physical breast examinations, and 19,694 women to the physical examination-only arm. All women were carefully trained to perform breast self-examinations. The women were followed from entry for an average of 13 years. Five annual screening examinations were offered to the first 62% of the women entering the study and four to the remainder. Nurses carried out the physical examinations in 12 of the 15 screening centers, and physicians performed the examinations in the other three. The examination, both physical and visual, took about 10 minutes. Two-view film-screen mammography was used at all screening centers, and a stratified random sample of all films was systematically reviewed by a single reference radiologist. Women with suspicious physical or mammographic findings were assessed by study surgeons who made appropriate recommendations to the family physicians. Over the screening period and subsequent follow-up period, 622 invasive breast cancers were detected in the mammography plus physical examination group, compared with 610 in the physical examination-only group. Linkage of study participants to the Canadian Mortality Data Base showed that through 1993 there were 88 deaths from breast cancer in the mammography plus physical examination arm and 90 breast cancer deaths in the physical examination-only arm. These results show that mammography was not associated with a reduction in breast cancer deaths even though mammography detected smaller cancers than physical examination did. The authors conclude that, for women older than 50 years, thorough annual physical breast examinations, plus teaching of breast self-examination, may be a useful alternative to mammography. The authors emphasize that physical examinations for screening involve far more skilled attention to relatively minor signs than those often rather casually performed by health-care workers who have not been trained to recognize the subtle physical signs of early breast cancer. Contact: Megan Easton, University of Toronto, (416) 978-5948; fax: (416) 978-1632. 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

Arnold, Katherine; Eckstein, Dan

doi: 10.1093/jnci/92.18.1455-bpmid: N/A

September 14, 2000 (EMBARGOED FOR RELEASE 4 P.M. EDT September 19) The largest known population-based study of hereditary nonpolyposis colon cancer (HNPCC) shows this form of colon cancer to be less common than sometimes reported. The study, conducted by David Peel, Ph.D., and Hoda Anton-Culver, Ph.D., at the University of California at Irvine, and colleagues, involved 1134 patients with colon cancer living in three counties of Southern California. Depending on age at diagnosis and geographic location, from 0.9% to 2.1% of the patients had a clinical history that met widely accepted criteria for HNPCC, compared with published estimates of HNPCC that range as high as 13%. These results are presented in the September 20 issue of the Journal of the National Cancer Institute. Patients diagnosed with colon cancer in 1994–1996 were identified through population-based cancer registries in Orange, San Diego, and Imperial counties of Southern California. About 70% of these patients agreed to participate in the study. In addition, 11 patients with known HNPCC were referred into the study and were used to study genetic characteristics of HNPCC. For the 767 participants who were diagnosed under age 65 years, data were collected on cancer diagnoses in more than 11,000 first- and second-degree relatives. A positive family history of colorectal cancer was defined as at least one first-degree relative or at least two second-degree relatives with colorectal cancer. The widely accepted Amsterdam criteria were used to define HNPCC families. Of the 1134 patients, 227 had a positive family history of colorectal cancer, and 16 patients, all diagnosed at under age 65 years, met the Amsterdam criteria for HNPCC. Endometrial cancer was moderately elevated in families of HNPCC patients, as was cancer of the ureter. Colorectal cancers that occurred either at the same time (synchronous) or at different times (metachronous) were elevated among the HNPCC families, with a prevalence rate of 12.5% as compared with 5.9% in non-HNPCC families with a positive family history of colorectal cancer and 2.6% in patients with a negative family history. Literature reports indicate that HNPCC-related tumors tend to occur most often in proximal locations. However, this was not true in either the 16 HNPCC patients identified in this study or the 11 case patients who were referred into the study. Five of the 11 referral HNPCC case subjects had a mutation in the MSH2 or MLH1 gene. The family members of patients with such mutations tended to show an earlier age at diagnosis of colorectal cancer and had more multiple primary cancers than those of patients without detectable mutations. The authors conclude that their work is not a final answer but rather a necessary first step for HNPCC prevalence figures in the general population, and they plan to complete a full molecular analysis in the near future. Contact: Andrew Porterfield, University of California at Irvine, (949) 824-3969; fax: (949) 824-2676. 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/92.18.1455pmid: N/A

13-Year Results of Canadian Breast Cancer Screening Trial Although mammography screening for breast cancer among women 50 years of age and older has been shown in several studies to reduce breast cancer deaths compared with no screening, the incremental effect of mammography screening over and above physical examination of the breasts is not known. Miller et al. (p. 1490), in a breast screening study in Canada, compared 39,405 women randomly assigned to receive either annual mammographic screening plus physical examination of the breasts or annual physical examination alone. All women were taught breast self-examination one-to-one by trained personnel. More breast cancers were detected in the group receiving mammography, but breast cancer deaths were equal in the two groups. These findings, after an average follow-up of 13 years, confirm early results from the same trial. The authors suggest that physical breast examination, combined with competent breast self-examination, may be an alternative to mammographic screening in women aged 50 years and older. “The Canadian National Breast Screening Study-2 is the only trial that has evaluated the effect of mammography over and above physical examination of the breasts and breast self-examination in women aged 50–59 years.” —Miller et al. Prevalence of Hereditary Nonpolyposis Colon Cancer Colon cancer is one of the most common forms of cancer in the United States, but it is not clear how much of the disease is an inherited form called hereditary nonpolyposis colon cancer, or HNPCC. Peel et al. (p. 1517) addressed this question by examining a population-based cohort of colon cancer cases in three counties of southern California. They based their ascertainment of HNPCC on incidence of colon cancer in first- and second-degree relatives. They collected additional data from patients with both sporadic and familial colon cancer and analyzed mismatch repair genes, finding a lower prevalence of mutations than in previous research. They estimated that, in their population, the prevalence of HNPCC among persons diagnosed with colon cancer was about 1%, a lower figure than estimated in other studies. Hypermethylation of the DAP Kinase Promoter and Lung Cancer Hypermethylation of the promoter for death-associated protein (DAP) kinase, an enzyme that is involved in programmed cell death, represses the expression of DAP kinase and is a common abnormality in early-stage non-small-cell lung cancer (NSCLC). Tang et al. (p. 1511) investigated whether the hypermethylation status of the DAP kinase promoter influences the prognosis of patients with NSCLC. In 135 patients with early-stage NSCLC, 59 had tumors with hypermethylated DAP kinase promoters. These patients had a statistically significantly poorer probability of overall survival 5 years after surgery than those without hypermethylation. In addition, the probability of 5-year disease-specific survival was strikingly better for patients without hypermethylation than for those with hypermethylation. The authors conclude that hypermethylation of the DAP kinase promoter is strongly associated with survival and that DAP kinase plays an important role in determining the biologic aggressiveness of early-stage NSCLC. In an accompanying editorial, Baylin et al. (p. 1460) consider the wider implications of epigenetic changes such as the hypermethylation of gene promoters both for understanding the mechanisms that drive tumorigenesis and as a molecular marker for the early detection of some cancers. “Multivariate analysis indicated that hypermethylation of the DAP kinase promoter is the only independent predictor for disease-specific survival among clinical and histologic parameters tested.” —Tang et al. HPV-Associated Malignancies in HIV Infection and AIDS Human papillomavirus (HPV)-associated anogenital malignancies occur frequently in patients with human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). Frisch et al. (p. 1500) investigated whether the high frequency of these cancers is due to lifestyle factors associated with both HPV and HIV infections or to HIV-induced immunosuppression. They studied in situ and invasive HPV-associated cancers, and they observed that all HPV-associated cancers in patients with HIV infection/AIDS occurred in excess compared with numbers expected in the general population. Increasing relative risks for in situ cancers to and beyond the time of AIDS onset, the authors conclude, may reflect the gradual loss of control over HPV-infected keratinocytes with advancing immunosuppression. They also note that the lack of a similar increase for invasive cancers suggests that late-stage cancer invasion is not greatly influenced by immune status. Risk of Hodgkin’s Disease After Infectious Mononucleosis Infectious mononucleosis is caused by the Epstein-Barr virus and has been known to be associated with an increased risk for Hodgkin’s disease. However, little is known about how infectious mononucleosis affects the long-term risk of Hodgkin’s disease or any other cancer, how this risk varies with age at infectious mononucleosis diagnosis, and how the risk for Hodgkin’s disease varies in different age groups. Hjalgrim et al. (p. 1522) followed population-based cohorts of patients with infectious mononucleosis in Denmark and Sweden for cancer occurrence. They found that, in addition to Hodgkin’s disease, only skin cancers occurred in statistically significant excess. The risk for Hodgkin’s disease remained elevated for up to two decades after the occurrence of infectious mononucleosis but decreased with time. Following infectious mononucleosis, the risk for Hodgkin’s disease was particularly increased at ages 15–34 years—more than three times higher than during any other age period. Oxford University Press Oxford University Press

Baylin, Stephen B.;Belinsky, Steven A.;Herman, James G.

doi: 10.1093/jnci/92.18.1460pmid: 10995795

In this issue of the Journal, Tang et al. (1) report that the presence of abnormal methylation in the 5` region of the death-associated protein (DAP) gene in tumor DNA predicts shorter survival in patients who had undergone surgery for non-small-cell lung cancer (NSCLC). This change in methylation is an example of an epigenetic process that is attracting increasing attention, both because of its potential significance to our basic understanding of cancer and because of its possible use for improved cancer diagnosis and treatment. However, the study by Tang et al. also raises many of the questions that constitute an ongoing vigorous, but constructive, debate as to the true biologic significance of these postreplicative DNA changes (2). “CpG islands” surround the transcription start regions of almost half of the genes in the human genome and are normally unmethylated. Hypermethylation of CpG islands in cancers is associated with transcriptional silencing of the genes in which this change occurs. “Association” is the operative word here because central to this debate is whether methylation initiates, or is even essential for, gene silencing. However, the main point of the study by Tang et al. involves CpG methylation as a molecular marker that may be independent of its functional implications. Indeed, as the authors imply, promoter hypermethylation is emerging as one of the most promising molecular strategies for early detection of cancer, independent of its role in tumor development. Methylation of CpG islands may act as a relatively simple “yes–no” signal for the presence of tumor when examined for under optimal assay conditions by sensitive polymerase chain reaction (PCR) techniques such as the one (3) used by Tang et al. When cancers, even of the same histologic types, are compared between individual patients, DNA mutations in genes such as p53 or mitochondrial genes (4) often involve myriad different base changes at many locations within the gene. In contrast, aberrant promoter hypermethylation always occurs in virtually the same location within an affected gene, allowing a single PCR primer to be applicable to all patients for examination of the methylation status of a specific gene. Most important, sites distant from primary tumors can then be studied without first examining tumor DNA from each individual patient. Further evidence of a useful diagnostic role for methylation is the finding that the hypermethylation changes for a given gene can be extremely frequent in a cancer type (5), as was found by Tang et al. for DAP in NSCLC. The number of genes known to be hypermethylated in cancer is also growing, and the ability to detect most tumor types with a relatively small panel of these markers is a distinct possibility. Proof of principle for these above possibilities is apparent in the recent finding (6) that hypermethylation markers are detected with high frequency and sensitivity in sputum DNA from patients with squamous cell lung carcinoma up to 3 years before clinical diagnosis (6). Tang et al. (1) suggest that DAP hypermethylation may be a marker for monitoring prognosis in patients with NSCLC. Certainly, as the authors point out, this possibility must be validated by additional larger studies. In this regard, it will be of interest to see how DAP hypermethylation may relate to other molecular alterations, such as p53 mutations, that might influence prognosis for patients with NSCLC. Why should methylation changes in the DAP gene be capable of providing this type of marker? It is possible that distinct patterns of epigenetic changes in this gene (or other genes) could simply accompany pathways to the evolution of certain tumor types that predict for their metastatic behavior. Alternatively, as the authors suggest, loss of function of a given hypermethylated gene may constitute the specific factor dictating tumor behavior. Indeed, DAP has been implicated in the metastatic potential of lung cancer in an experimental model (7). Moreover, a recent study (8) found an association between the presence of DAP hypermethylation and lymph node involvement in patients with head and neck cancer. Finally, the DAP gene encodes a protein that mediates apoptotic response, and reactivation of a hypermethylated DAP gene can restore interferon-induced apoptosis in tumor cells (9). The possibility that DAP function determines tumor behavior points to the critical questions about the significance of promoter hypermethylation in cancer (2). Do such changes really signify biologically important events? In properly demanding more concrete data to answer this question, participants in the debate often fail to examine the selective advantage of hypermethylation (2). This is a most fundamental biologic principle for suggesting the functional significance of any given DNA change and, for the patterns of hypermethylation of bona fide tumor suppressor genes in cancer, such selective advantage tracks exceedingly well with predictions of biologic importance (5). Indeed, the hypermethylation changes often mimic the patterns for mutations in these same genes. For example, both genetic and epigenetic alterations of the VHL, BRCA1, and STK11 genes are restricted to the same specific tumor types (5,10). Also, there is an absolute inverse relationship, in tumors of multiple types, between genetic disruption of the Rb gene and both genetic or hypermethylation changes for the p16INK4a gene (5). In addition, loss of gene function in the presence of promoter methylation can be associated with the predicted phenotypic consequence, i.e., MLH1 and the microsatellite instability phenotype in colon carcinoma (11). Thus, whether or not the methylation is fully responsible for transcription silencing of a hypermethylated gene, this change seems hard to refute as a signature for the mechanisms responsible for loss of gene function when selective advantage is carefully examined. Does every promoter hypermethylation change in tumors signify a biologically important event? The answer is almost certainly “no.” However, one might best view the problem with the same eye as one views the consequences of a change, such as germline or somatic mutations, in the mismatch repair genes. These latter events as biologic processes certainly contribute directly to tumorigenesis, yet only occasionally is the coding region of a key gene involved. Instead, the clonal presence of mutations in the repair genes reflects the global importance of the defective repair process, rather than the contribution of the majority of the resultant mutations, to tumor development. If promoter hypermethylation can disrupt the function of critical genes, what explains, at a molecular level, the associated gene silencing? This question has plagued the field of DNA methylation since its inception. Recent research suggests intriguing possibilities. Through methylcytosine-binding proteins, DNA methylation may recruit transcriptional corepressors and histone deacetylases that are critical for the composition of transcriptionally repressive chromatin (12). For hypermethylated cancer genes, the methylation appears dominant over the histone deacetylation activity in the process of repression (13). Furthermore, enzymes that establish DNA methylation are now appreciated as complex proteins that, independent of their methylating properties, have intrinsic transcriptional repression activity, the ability to target transcriptional corepressors, and the potential to regulate histone deacetylation in newly forming chromatin (14–16). Recent evidence (17) suggests that, in some cancer types, more than one such enzyme may be important for tumor gene hypermethylation. It will thus be important to define the precise complexes that repress the transcription of specific genes hypermethylated in cancer, with the possibility that they could have a role in actually causing the abnormal methylation patterns. In summary, epigenetic events may be comediators with genetic alterations to drive tumorigenesis. Hypermethylation changes may be excellent tumor markers—and, as Tang et al. (1) note, the reversible nature of epigenetic gene silencing makes this process an attractive target for cancer therapy. Much has been learned, much remains unanswered, and only future results in both basic and clinical research will reveal the ultimate impact of findings to date for the understanding and control of cancer. References 1 Tang X, Khuri FR, Lee JJ, Kemp BL, Liu D, Hong WK, et al. Hypermethylation of the death-associated protein (DAP) kinase promoter and aggressiveness in stage I non-small-cell lung cancer. J Natl Cancer Inst  2000; 92: 1511–6. Google Scholar 2 Fearon ER. BRCA1 and E-cadherin promoter hypermethylation and gene inactivation in cancer-association or mechanism? J Natl Cancer Inst  2000; 92: 515–7. Google Scholar 3 Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A  1996; 93: 9821–6. Google Scholar 4 Fliss MS, Usadel H, Caballero OL, Wu L, Buta MR, Eleff SM, et al. Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science  2000; 287: 2017–9. Google Scholar 5 Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet  2000; 16: 168–74. Google Scholar 6 Palmisano WA, Divine KK, Saccomanno G, Gilliland FD, Baylin SB, Herman JG, et al. Predicting lung cancer by detecting aberrant promoter methylation in sputum. Cancer Res. In press 2000. Google Scholar 7 Inbal B, Cohen O, Polak-Charcon S, Kopolovic J, Vadai E, Eisenbach L, et al. DAP kinase links the control of apoptosis to metastasis. Nature  1997; 390: 180–4. Google Scholar 8 Sanchez-Cespedes M, Esteller M, Wu L, Nawroz-Danish H, Yoo GH, Koch WM, et al. Gene promoter hypermethylation in tumors and serum of head and neck cancer patients. Cancer Res  2000; 60: 892–5. Google Scholar 9 Katzenellenbogen RA, Baylin SB, Herman JG. Hypermethylation of the DAP–kinase CpG island is a common alteration in B-cell malignancies. Blood  1999; 93: 4347–53. Google Scholar 10 Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, et al. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst  2000; 92: 564–9. Google Scholar 11 Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A  1998; 95: 6870–5. Google Scholar 12 Bird AP, Wolffe AP. Methylation-induced repression—belts, braces, and chromatin. Cell  1999; 99: 451–4. Google Scholar 13 Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet  1999; 21: 103–7. Google Scholar 14 Fuks F, Burgers WA, Brehm A, Hughes-Davies L, Kouzarides T. DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat Genet  2000; 24: 88–91. Google Scholar 15 Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP. DNMT1 forms a complex with rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet  2000; 25: 338–42. Google Scholar 16 Rountree MR, Bachman KE, Baylin SB. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet  2000; 25: 269–77. Google Scholar 17 Rhee I, Jair KW, Yen RW, Lengauer C, Herman JG, Kinzler KW, et al. CpG methylation is maintained in human cancer cells lacking DNMT1. Nature  2000; 404: 1003–7. Google Scholar © Oxford University Press

Baylin, Stephen B.; Belinsky, Steven A.; Herman, James G.

doi: N/Apmid: N/A

Garber, Ken

doi: 10.1093/jnci/92.18.1462pmid: 10995796

In the quarter century since the appearance of the original Nature paper on monoclonal antibodies, optimism about their therapeutic value has waxed and waned. These key immune system proteins have evolved from laboratory novelties to overhyped “magic bullets” to discards on the garbage heap of failed therapies. Only in the last few years, with U.S. Food and Drug Administration approval of Rituxan and Herceptin, has their image as therapeutic agents begun to recover the old shine. Burnished by a series of scientific innovations, monoclonal antibodies may be poised for a renaissance. Like many breakthroughs, the discovery of monoclonal antibodies was serendipitous, not intentional. César Milstein, Ph.D., an expatriate Argentine immunologist working at the Medical Research Council laboratories in Cambridge, England, was trying to decipher the mechanism of antibody diversity—how the body quickly generated antibodies to foreign substances, or antigens. He used antibody-secreting mouse myeloma cells because normal B cells do not survive long in culture. Swiss immunologist Georges Kohler, Ph.D., after joining Milstein’s laboratory, tried to grow myeloma cells capable of recognizing antigens (he failed) and then fused myeloma cells to see if they produced antibodies from both parent cells (they did). It then occurred to Milstein and Kohler to try fusing normal B cells with myeloma cells to immortalize the B cells and produce a steady stream of identical (monoclonal) antibodies. “To our surprise, the experiments were a resounding success,” Milstein later recalled. “If my research aim . . . had been the production of monoclonal antibodies, I would never have stumbled on the idea.” ‘A Huge Future’ The Nature paper generated little excitement at first, but some researchers immediately grasped the potential of monoclonal antibodies. “I was just over the top when I read it,” recalled Ellen Vitetta, Ph.D., an immunologist at the University of Texas Southwestern Medical Center in Dallas. “I read it three times. . . . I realized there was going to be a huge future in using these reagents both diagnostically and clinically.” The Nature paper’s last sentence (“Such cultures could be valuable for medical and industrial use”) Vitetta called “the understatement of the century.” The Medical Research Council, not seeing any commercial potential in monoclonal antibodies, chose not to patent the discovery. “It was a very good thing they didn’t, because it let the whole technology really flourish,” said Vitetta. “It probably launched a gazillion dollar industry.” The event that sparked the epochal hope (and hype) of the 1980s was the treatment by Ronald Levy, M.D., of a gravely ill lymphoma patient with a tailor-made mouse anti-idiotype antibody in 1981. The patient made a complete recovery, and is still alive today. Although Levy, a professor at Stanford University’s School of Medicine, later abandoned the anti-idiotype approach, he had shown that a monoclonal antibody could cure cancer. Companies formed to develop monoclonal antibody-based therapies, and the National Institutes of Health poured money into academic translational research. The press touted monoclonal antibodies as “magic bullets” that could target tumors without side effects. A Shortcoming Unfortunately, most monoclonal antibodies were a colossal failure as therapy. Truly unique tumor antigens do not exist, so side effects were inevitable and often serious. Antibodies’ large size kept them from penetrating deep into tumors. Attempts to conjugate antibodies with various toxins to add potency made them unstable in the bloodstream and often blocked the antigen binding site, rendering these “immunotoxins” useless. The worst problem was that monoclonal antibodies came from mice. (Fusing human B cells with mouse myeloma cells does not work because the human chromosomes disappear, and so far no suitable human myeloma cell line has been found.) Mouse-derived antibodies did not mobilize the human immune system very well, and they provoked a strong immune reaction against themselves when injected into people. This blunted their effectiveness, precluded repeat treatments, and made patients sicker. Once these facts became apparent, industry soured on monoclonal antibodies. “Interest diminished and diminished,” recalled National Cancer Institute immunotoxin researcher Ira Pastan, M.D. The early monoclonal antibody companies sold out in the mid-1980s. Failures in sepsis trials and a disastrous 1993 trial of the monoclonal antibody Campath 1H for arthritis further sullied the reputation of monoclonal antibodies. Only one therapeutic monoclonal antibody, OKT3 for the prevention of organ transplant rejection (1986), received FDA approval before 1994. By the early 1990s, however, innovations in the laboratory had started the pendulum swinging back. Scientists, including Pastan, developed better ways of using recombinant DNA technology to link antibodies to toxins. They also reduced their size to better penetrate tumors. Most importantly, genetic engineering enabled a frontal attack on the mouse problem: In 1984 “chimeric” antibodies, consisting of a mouse variable region and human constant region, were unveiled. Three years later saw the arrival of “humanized” antibodies, which are entirely human except for the precise antigen-binding site. Finally, in 1996, two companies—Abgenix, Foster City, Calif., and GenPharm, Mountain View, Calif. (now Medarex, Annandale, N.J.), created fully human antibodies from transgenic mice engineered to express human immunoglobulin gene sequences. “Humanization has really rewritten the book on these [monoclonal] agents,” said Ed Sausville, M.D., Ph.D., associate director for NCI’s Developmental Therapeutics Program. “You can give them repeatedly, they are well-tolerated, they successfully deal with the anti-antibody responses, in most cases.” Slow in Popularity Acceptance took time. In the late 1980s, “there were pockets of people who believed that an antibody could be an effective therapy,” recalled John Mendelsohn, M.D., now president of the University of Texas M. D. Anderson Cancer Center, Houston. But the believers, mostly in academia, faced heavy resistance from companies. The story of how oncologist Dennis Slamon, M.D., Ph.D., of the University of California at Los Angeles, personally drove the development of Herceptin despite long hesitation on the part of Genentech, South San Francisco (which owned the drug), is now well known. Mendelsohn also struggled to interest a company in his own antibody, a cousin to Herceptin. In the early 1980s, he theorized that an antibody blocking the EGF receptor, a key signaling molecule overexpressed on the surface of about one-third of epithelial tumors, could arrest tumor growth. “There was a period of about 4 years where we were delayed because the company [Eli Lilly] that had the license really didn’t want to take it forward,” Mendelsohn recalled. Eventually, Lilly (Indianapolis) reassigned the patent rights to the University of California. A small New York biotech company, ImClone, licensed the drug, C225, and began clinical trials in the early 1990s. Now in phase III trials, C225 may prove even better than Herceptin. In one phase II trial for head and neck cancer, C225 combined with radiation achieved a 100% response rate, including complete remissions in 13 of 15 patients. It also worked well combined with chemotherapy. Different treatments may synergize, killing tumors through separate apoptotic pathways, said Mendelsohn. Wave of Approvals If C225 wins FDA approval, it will ride a cresting wave of product launches. Since November 1997, the FDA has approved eight monoclonal antibody-based drugs for marketing. The latest is Wyeth-Ayerst’s (Madison, N.J.) Mylotarg, an anti-CD33 antibody linked to the antibiotic calicheamicin, for treating relapsed acute myelogenous leukemia. Others are on the way. Two radiolabeled antibodies, IDEC Pharmaceuticals’ (La Jolla, Calif.) yttrium-linked Y2B8 and Coulter Pharmaceuticals’ (South San Francisco) iodine-conjugated Bexxar, have completed impressive phase III trials for non-Hodgkin’s lymphoma. Bexxar, for example, has an overall response rate of 70% with complete remissions in 30% of relapsed patients with the especially deadly low-grade form of the disease. (As first-line therapy, Bexxar is even better.) “It is too soon to tell if Bexxar cures anybody, although we have seen . . . ongoing complete remissions of 5 to 7 years in chemotherapy-failed patients,” says Bexxar co-inventor Mark Kaminski, M.D., of the University of Michigan, Ann Arbor. Antibodies linked to natural toxins like ricin or Pseudomonas toxins are not nearly as far along, but some of these immunotoxins have done well. Pastan’s BL22 recently produced complete remissions in six out of seven patients with hairy cell leukemia and could begin a pivotal trial in various leukemias and lymphomas soon. But serious obstacles remain in linking toxins to the antibodies. Although the linked antibodies are better, “stability of the linkage is going to be an issue” when mass-producing immunotoxins, said Sausville. Many immunotoxins still cause serious toxicity, especially “vascular leak syndrome,” a devastating inflammation of the blood vessels. Naked antibodies like Rituxan and Herceptin are safer, but not very effective alone. “As single agents, they don’t have a lot of activity,” said Sausville, who sees far more potential in combination use with chemotherapy and radiation, and eventually together with small molecule drugs and vaccines. Those trials will be expensive and could take decades to complete. The pharmaceutical industry, historically averse to large molecule drugs like antibodies, may be changing. Abgenix supplies its “Xenomouse” to virtually all big drug companies. “I see [antibody research] only continuing to grow,” said Matt Sherman, M.D., head of clinical oncology R&D for Wyeth-Ayerst. “If you have an antigen, and generate an antibody, that very often is the final product. You can generate that quickly, and have it available for clinical testing. And you don’t need to know what the target actually does.” What of the future? Many variations on the monoclonal antibody theme are in advanced development: bispecific antibodies that attach both to tumor and to an effector cell or toxic molecule; antibody dimers, which deliver strong apoptotic signals to the target; new drug-antibody conjugates like Mylotarg; and antibody mimetics, synthetic peptides that more easily penetrate tumors. “We’ve now got one that’s better than Herceptin,” said the University of Pennsylvania’s Mark Greene, M.D., Ph.D. The field “has just become potentially more rich and diverse in terms of the opportunities than certainly we dreamed of even a short time ago,” said Sausville. “We’re really limited only by our imagination.” Many of the pioneers, like Vitetta, Mendelsohn, and Greene, are still working. “What keeps me going? I know this is going to work,” said Vitetta. “I can see it in my mice, I can see it in my cells. And I know it’s going to help humans. And I just can’t let it go until I prove that.” Open in new tabDownload slide Dr. Ellen Vitetta Open in new tabDownload slide Dr. Ronald Levy Open in new tabDownload slide Dr. Ira Pastan Open in new tabDownload slide Dr. John Mendelsohn Oxford University Press Oxford University Press

Fintor, Lou

doi: 10.1093/jnci/92.18.1464pmid: 10995797

The three pillars of cancer treatment—surgery, chemotherapy, and radiation—are being augmented and in some cases replaced by a new twist on an old idea: destroying tumors by flash freezing. Debuting in the 1960s, cryosurgery was initially viewed as a promising new method of attacking cancer cells, but clinicians soon discovered they had difficulty guiding and controlling the freezing process. Such imprecision often resulted in the destruction of too much adjacent normal tissue, and the technique was quickly abandoned. But by marrying military technology developed to cool missile guidance systems with advances in medical imaging such as ultrasound, computerized tomography, and magnetic resonance imaging, cryosurgery is emerging as not only a viable but in some cases a more favorable alternative for treating cancers of the prostate, breast, liver, and kidney. Less Invasive Approach “In the last 2 years there has been a change in the mentality of doctors, and I see this as continuing as the whole field moves toward minimally invasive procedures,” said Aaron Katz, M.D., assistant professor of urology at Columbia University’s College of Physicians and Surgeons. “The old-time urologists who think the only way to cure cancer is with a knife are a dying breed.” Cryosurgery of the prostate is generally done at temperatures below –40°C with the use of hollow probes that are inserted into the gland to deliver and circulate a freezing agent, liquified argon gas, directly to the tumor and affected tissues. As a ball of ice crystals begins to form around the tips of the probes, a warming catheter inserted through the urethra protects surrounding tissue. The procedure requires precise placement of the probes using imaging technology, and thermosensors can be used to monitor tissue temperatures while a “freezing-thawing” process is repeated before the probes are withdrawn. The procedure takes about 2 hours, and the dead prostate tissue shrinks and is dissolved naturally. In July 1999, the U.S. Health Care Financing Administration granted Medicare reimbursement for cryosurgical procedures involving primary, localized prostate cancer after reviewing evidence that the procedure is safe, effective, and comparable to radiation therapies such as external beam and brachytherapy (the implantation of radioactive pellets or “seeds” in the prostate gland). In addition, proponents maintain that because the procedure is less invasive and time consuming than other approaches there are fewer risks, faster recovery, less morbidity, and a high degree of cost-effectiveness. Cost and Outcome Advantages According to HCFA, the cost of prostate cancer cryosurgery is approximately $13,500, compared with $14,200 for brachytherapy, $15,000 for external beam radiation and at least $10,600 for radical prostatectomy. Prior to Medicare approval, about 80 private insurers offered coverage for cryosurgery with about 10% limiting reimbursement to radiation failure. Still, more than 75% of all treatments last year were for initial versus “salvage” treatment following radiotherapy. With more than 80% of those diagnosed with prostate cancer older than 65 years and 16 million male Medicare beneficiaries, the market potential is enormous. Katz, who is also a clinician at New York’s Columbia-Presbyterian Medical Center, has performed more than 200 of the procedures, noting that referrals from community physicians for patients with localized tumors are increasing as patients demand less invasive treatment. Cryosurgical ablation uses a minimal amount of anesthesia, it kills tumors growing outside the prostatic capsule, and blood loss is minimal, Katz said. In addition, it usually requires only an overnight hospital stay and patients can often resume normal activities within a few days. Five-year-survival rates appear at least comparable to other treatment modalities, and rates of urinary incontinence sometimes associated with radical prostatectomy and external beam radiation are reduced from at least 23% and 10%, respectively, to approximately 1% to 4%— similar or better than brachytherapy estimates. Perhaps even more important, it is not only repeatable but can be a viable option among patients who are poor candidates for surgery or radiation due to their age or because they have other chronic conditions such as heart disease. But existing freezing technologies do affect the neurovascular bundle. At least half of those treated report impotence as the most prominent side effect, while about 22% to 29% of those undergoing external beam radiation, 60% to 89% of those undergoing radical prostatectomy, and up to 50% of those undergoing brachytherapy report a similar outcome. Breast Cancer Application? It now appears that cryosurgical technology may have even broader applications. Last month a Canadian team reported that using cryosurgery to treat breast cancer in women who were referred for breast surgery resulted in total destruction of the tumors in eight of nine women and partial tumor destruction in the remaining patient. Study investigator Christian Moisan, Ph.D., head of the interventional MRI program at Quebec City University Hospital, cautioned that while the sample size is quite small and results are very preliminary, they are nevertheless extremely encouraging. “What we really care about is being able to predict assuredly that the cancer has been completely destroyed using the technique, and we are finding that we have been able to anticipate complete destruction of the tumor with a high degree of success,” Moisan said. The study is limited to women with localized breast cancer who agree to delay surgery for one month to undergo the cryosurgical procedure using interventional MRI guidance. One month later they undergo scintillation mammography to determine the extent of tumor destruction, and then standard treatment, such as lumpectomy or mastectomy with adjuvant treatment, is resumed. Images of the breast after cryosurgery and after standard surgeries are then compared. The breast cryosurgery procedure takes about 3 hours with 1 hour for recovery and can be done on an outpatient basis, Moisan said. Liver, Renal Cancers Cryosurgery’s most dramatic benefit may be in those who cannot undergo standard surgical treatment because of their age or other debilitating conditions and in cases of inoperable liver cancers, which is among the other avenues Moisan’s team is pursuing. “There is a very strong need for new curative options for patients who would otherwise face a grim course,” Moisan said. “New applications like MRI-guided cryosurgery of the liver are becoming viable options for those who would otherwise have none.” In addition, similar technology was used to perform the first renal cancer cryosurgery using interventional MRI at the University of Mississippi in May 1999. The localized tumor of a 72-year-old man was ablated by freezing followed by laser warming while clinicians watched the tissue being destroyed in real time. The patient had one kidney surgically removed due to the same cancer in 1997, and his only alternative was the surgical removal of his remaining kidney. He was discharged the following day and allowed to resume normal activities almost immediately. At present only a handful of companies are in the cryosurgical market. These include Irvine, Calif.-based Endocare Inc., Galil Medical Ltd. of Israel, and Cryomedical Sciences Inc. of Rockville, Md. “Percutaneous and less invasive approaches will eventually replace surgery as the discussion focuses on quality of life issues,” predicted Paul Mikus, Ph.D., Endocare’s president and chief executive officer. “The advantage that cryo[ablation] has over all new percutaneous methods is the ability to see the ablation encompass the tumor, and it is a significant advantage.” Open in new tabDownload slide The Cryo-HIT machine, manufactured by Galil Medical, integrates a cryotherapy system with interventional MRI. Real-time guidance of the specially designed probes ensures that a surgeon can direct the probes to the target tissue. The frozen region is clearly seen with the MRI, therefore only unwanted tissue is ablated. Open in new tabDownload slide Dr. Paul Mikus Oxford University Press Oxford University Press

Kuska, Bob

doi: 10.1093/jnci/92.18.1466pmid: 10995798

In 1935, a nutritionist at Cornell University named Clyde McCay reported that in a series of experiments involving laboratory rats, he found that those eating a low-calorie, high-nutrient diet lived several months longer than their normally fed cage mates, a major improvement in lifespan for these short-lived animals. The implication being: cut calories, live longer. As the years passed, many molecular biologists have remained skeptical of the finding. Like the line from the movie Jerry Maguire, “Show me the money,” molecular biologists have demanded, “Show us the mechanisms.” And that is where the conversation came screeching to a halt. With limited data and laboratory tools at their disposal, scientists could not even begin to contemplate how to isolate the cellular mechanisms influenced by caloric restriction. But that could soon change in the new century. Pointing to the arrival of genomics and higher-powered laboratory technologies, scientists say the field is now poised to systematically explore how a calorie-reduced diet affects many of the most basic processes of life, such as hormone secretion, gene expression, DNA repair, oxidative stress, and apoptosis. Although there is a mountain of work to be done, researchers say they are optimistic that these studies will play a leading role in helping to link molecular biology, genetics, and nutrition, a meeting of the minds that would greatly benefit cancer research. When Susan Perkins, Ph.D., steps into the animal room near her laboratory at the National Cancer Institute-Frederick Cancer Research and Development Center, in Frederick, Md., she said it is easy to spot the mice that eat a calorie-restricted diet. “The caloric-restricted mice jump up and down,” said Perkins. “They are extremely active because they are hungry.” Hungry for a good reason. Animals on calorie-restricted diets typically eat once a day and consume 30% to 50% fewer calories combined from fat, protein, and carbohydrates than their normally fed cage mates. If calories drop more than 50%, scientists say the animals will begin to show signs of malnutrition. Within the “healthy” range, though, the animals tend to live long and exceedingly ravenous lives. Most are slow to develop typical aches and pains of aging. “Caloric restriction is still the only intervention that is known to increase the median lifespan in animals,” said Perkins. That includes mice with tumors. Starting with the seminal work of Moreschi in 1909, scientists have reproducibly reported over the last 90 years that rats and mice with transplanted, spontaneous, or chemically induced tumors live longer when fed a calorie-reduced diet. In fact, rodents with tumors also often live longer on a calorie-reduced diet than their normally fed, cancer-free counterparts. But, like all of the “miracle” mouse studies that dot the scientific literature, cancer researchers have always walked a fine line between hope and hype when interpreting work on caloric restriction. They say that, intuitively, it makes sense that a low-energy diet might stress energy-guzzling cancer cells, impeding their ability to grow. Age More Slowly It also seems reasonable that when cells are forced to conserve energy, the organism will age more slowly. “Caloric restriction makes good evolutionary sense,” said Julian Leakey, Ph.D., a scientist with the National Center for Toxicological Research in Jefferson, Ark. “It is a mechanism that allows you to adapt your lifespan and reproductive potential to the environment for the benefit of the species. It gives you the dynamic to reproduce like mad when conditions are good, but survive otherwise.” Does this theory also translate to fact in people? Nobody knows. Because people live decades longer than rodents, which makes studies logistically and financially a tall order, human data are scarce in the literature. But, for now, scientists seem to have found an experimental middle ground on which to approach this major question. In 1989, the National Institute on Aging established the first of two large colonies of calorie-restricted rhesus monkeys, a close evolutionary cousin to humans. The monkeys, which started the diet at age 10 and are now approaching their mid 20s, will likely live about 40 years. Richard Weindruch, Ph.D., a scientist at the University of Wisconsin at Madison who oversees one of NIA’s calorie-restricted monkey colonies, said the final results of the study are still at least 15 years off. He said these final data will help to pin down the big-ticket health issues, including the effects of a calorie-restricted diet on longevity and age-related diseases, including cancer. Weindruch noted that so far, the preliminary data seem to support the pros of caloric restriction. He said many rhesus monkeys tend to develop adult onset diabetes, but, so far, the calorie-restricted monkeys have a much lower rate of the disease than those in the control group. The same holds true for signs of spinal osteoarthritis, a common age-related problem in rhesus monkeys. The scientists are also carefully monitoring body composition, metabolic rates, and indicators of oxidative stress. Show Us the Mechanisms Already, the first inroads have been made in generating a genomic profile of caloric restriction. A year ago, Weindruch and his colleague Tomas Prolla, Ph.D., a geneticist at the University of Wisconsin, published a profile of genes expressed in cells from normally fed young and old mice compared with those that consumed a calorie-restricted diet. Weindruch said this initial comparison, generated from an Affymetrix array of 6,500 mouse genes, was performed in non-dividing skeletal muscle cells. “The first data set compared the young and the old animals, then about 2 weeks later, we got the data on caloric restriction,” said Weindruch. “It was incredibly exciting because nearly all of the genes that were getting messed up with aging—either going up or down in transcription activity—were almost all being prevented by caloric restriction. It was just picking them off one at a time.” Although this study was only a first step, Weindruch predicts that subsequent genetic profiling studies will generate a wealth of leads into the biology of aging. “Aging is a very complex phenomenon, and caloric restriction induces hundreds, if not thousands, of biological changes,” he said. “Though this complexity is unwanted, that should not prevent one from using it as a window to explore the biology of aging.” Many contend that decades of research already have placed several excellent hypotheses on the table. One is that increased production of a stress-reducing hormone glucocorticoid mediates the anti-aging effects of caloric restriction. Other viable theories involve proposed changes in oxidative stress, DNA repair, apoptosis, T-cell–mediated immune responses, and other fundamental biologic processes. Big Picture Some note that the greatest challenge of all may be simply overcoming the reductionistic mindset that dominates modern biology. “What’s happened over the years in caloric restriction is different people have jumped on different bandwagons,” said Leakey. “Everybody is looking at it from their own fields, but the whole concept is more dynamic than that. Sometimes, you need to step back and look at the big picture.” As microarrays and other more powerful technologies pave the way to seeing the big picture, some warn that the field may find itself fending off the same shrug of the shoulders that greeted their predecessors. “We still struggle with the few who say this isn’t relevant to people because we are ‘starving’ our animals in order to get these effects,” said Diane Birt, Ph.D., a scientist at Iowa State University in Ames. “I really think that we have biological effects in ranges of consumption that are deemed to be healthy human consumption.” Birt and others also respond that research on caloric restriction extends far beyond the single question of “to eat or not to eat” a low-calorie diet. Speaking hypothetically, Birt said it may be that the field’s greatest future harvest may be diagnostic. “I think we need to go after baseline indicators of optimal health,” she said. “Biomarkers that will give us a handle on how much an individual should eat, expecting that it is going to differ depending on one’s genetic profile. We need to continue to get more information on how hormones, diet, and genetic predisposition influence gene expression.” In this age of designer drugs, Weindruch added that the field’s harvest could also be in therapeutics. “In rodents, where we know that caloric restriction retards aging and a broad spectrum of diseases—including cancer—we really need to understand the underlying mechanisms of those effects,” he said. “The importance there is it may allow for the development of caloric restriction mimetics, where one could find drugs or other interventions to mimic the critical effects of caloric restriction.” Leakey said the take-home lesson from caloric restriction already may be abundantly clear for people who live in affluent Western nations. That message is: Eat less. However the story plays out in caloric restriction, most scientists agree that the field will begin to wrap its fingers around the cellular mechanisms that have been so elusive for so long. “Oh, it’s as exciting as can be,” said Weindruch, who has studied caloric restriction since the 1970s. “The field has grown and will continue to grow tremendously.” Open in new tabDownload slide Dr. Susan Perkins Open in new tabDownload slide Dr. Richard Weindruch Open in new tabDownload slide Dr. Diane Birt Oxford University Press Oxford University Press

doi: 10.1093/jnci/92.18.1468pmid: 10995799

Open in new tabDownload slide Oxford University Press Oxford University Press

Jones, Jemarion

doi: 10.1093/jnci/92.18.1469pmid: 10995800

You can’t believe everything you read. Nowhere is this more true than with information on the Internet. For example, a number of wild rumors associated with various types of cancer have made the rounds on the Internet. One rumor claimed that common antiperspirants, used mostly by women, cause breast cancer. Circulated via e-mail, the rumor has been around for months, possibly years. It claims that antiperspirants are the leading cause of breast cancer and that antiperspirants prevent the body from purging toxins that can then deposit in the lymph nodes, where they can produce cancer-causing mutations. Most experts in breast cancer research say there is nothing to this rumor. There are no epidemiologic studies to support the idea that antiperspirant use is a risk factor. Additionally, the lymphatic system does clear some toxins, but the liver and kidneys play a more crucial role in purging substances from the body. More substances leave the body through urination than through perspiration. “There’s no proof to my knowledge that antiperspirants cause breast cancer,” said Jeff Abrams, M.D., of the National Cancer Institute’s Cancer Therapy Evaluation Program, adding that “these rumors . . . have the potential to do harm.” The “harm” is that the rumor alarmed enough people that several medical and health information organizations issued rebuttals to the e-mail’s claims. NCI, when asked, states that it is not aware of any research that supports a link between antiperspirant use and breast cancer. The U.S. Food and Drug Administration does not have evidence to support the claims. Additionally, the American Cancer Society, the Canadian Cancer Society, and the Susan G. Komen Breast Cancer Foundation have all posted statements denying any link between traditional breast cancer risk factors and the use of antiperspirants. Holding for an Answer Another health concern showing up in e-mail inboxes is a warning that cellular phones cause brain cancer. According to a recent Gallup poll, almost half of all Americans own a cellular phone, and there is a growing concern that all that talking could pose a serious health risk. Unlike the antiperspirant rumor, which major health establishments actively debunk, the jury is still out on whether talking on a cellular phone can be hazardous to health. As a result of conflicting reports and overall lack of information, the FDA announced in June that it would collaborate with the Cellular Telecommunications Industry Association to research mobile phone safety. At issue is whether radio frequency (RF) emissions from mobile phones have an adverse effect on human beings. According to the FDA and the World Health Organization, there is no evidence to date that proves mobile phone usage poses a health risk; however, there is not enough information currently available to totally rule out the possibility. “Results from the first large studies are in the process of coming out,” said Peter Inskip, Sc.D., of NCI’s Division of Cancer Epidemiology and Genetics. “By the end of this year or early next year, we should have more information relevant to these concerns.” He pointed out that cellular phones have not been widely available for a long period of time, making it too early to assess the long-term risks of cellular phone use. On Aug. 1, CTIA began requiring mobile phone manufacturers to disclose how much radiation from their cellular equipment could enter a user’s brain under laboratory conditions. The Federal Communications Commission already requires phones to meet safety standards. Soy Foods The health benefits of soy have recently gotten a lot of notice. However, e-mail campaigns have warned that overconsumption of soy can lead to an increased risk of breast cancer. Scientists, however, are quick to dismiss these claims. “There is no data to suggest that soy increases the risk of breast cancer,” said Worta McCaskill-Stevens, M.D., of NCI’s Division of Cancer Prevention, who is also the program director for the Study of Tamoxifen and Raloxifene. “A high level of soy food products, which contain isoflavones [plant chemicals], is thought to reduce the risk of breast cancer. Studies have shown high levels of isoflavones among Asian women [in Asia] in which the breast cancer rates are among the lowest in the world.” Ovarian Cancer and CA-125 Another Internet rumor comes in the form of a personal testimonal from a woman who claims she was not properly diagnosed with ovarian cancer until she received the CA-125 (tumor marker) blood test. After describing the experience, the e-mail goes on to urge women to insist on the test as a part of their annual physical exam. According to the experts, this is yet another case of misinformation transmitted via the Internet. “CA-125 is neither sufficiently sensitive or specific to be a good screen for ovarian cancer,” said Edward Trimble, M.D., head of the surgery section in NCI’s Cancer Therapy Evaluation Program. “Among premenopausal women, conditions such as endometriosis, uterine fibroids, and menstruation can cause CA-125 elevations.” According to Trimble, the CA-125 test was approved by the FDA only for monitoring the response to chemotherapy in women with advanced or recurrent ovarian cancer; it was not approved for diagnosis. Does Everything Cause Cancer? Shampoo, underwire bras, and NutraSweet have all been identified by e-mail as contributors to cancer. Health experts and health organizations are quick to deny any truth to these rumors. “Part of the problem is that some rumors hold just enough logic to sound convincing to anyone who is not an expert,” said Steverna Fields, who heads NCI’s Public Inquiries Office. “It’s understandable that the average lay person may not know the difference.” “There continues to be voids in the fund of knowledge about cancer,” added McCaskill-Stevens, “such that a little bit of erroneous information can further alienate women who are in the greatest need of facts about cancer.” Open in new tabDownload slide Dr. Jeff Abrams Open in new tabDownload slide Dr. Worta McCaskill-Stevens Oxford University Press Oxford University Press