by Harry Brodie
(Issue 10 · posted June 13, 1997; archived June 27, 1997)
Approximately 7,500 scientists gathered April 12-16 in San Diego to attend the American Association of Cancer Research's 88th annual meeting. In listening to papers and exchanging views on the current state of research, it became apparent that this year workers had to be content with small, but still significant, advances. There was no euphoria to be found as when AIDS researchers reported the dramatic effects of protease inhibitors on that virus. Nevertheless, the organization leaders were upbeat about the continued progress being made, especially in the area of identifying oncogenes and how they work.
The meeting opened with an ambitious 2.5-hour public forum on the theme of progress and hope. The forum also initiated a drive led by AACR's charismatic new president, Donald Coffey of the Johns Hopkins University, to obtain more public money for cancer research. He said, "We are not yet in a war on cancer but only a skirmish, and we want two more bombers to help make it a war," equating one bomber to a billion more dollars for research.
The forum attracted about 750 cancer survivors, their friends and relatives, and lay activists from the southern California area. While the audience came mainly to be educated, some of the activist element aggressively asked why the cancer establishment was keeping effective drugs off the market and why it was opposed to alternative medical approaches. Panel members pleaded not guilty to both charges, stating that such rejected approaches lack valid clinical trial evidence to support them.
The session focused on recent advances in breast, prostate, and lung cancer, in that order. As the speakers moved from one topic to the other, advances became fewer, although hope for the future remains strong.
Marc Lippman of Georgetown University, speaking about breast cancer, emphasized that all human breast cancer is due to one or more genetic defects, and that 10% of breast cancers are due to defects in breast cancer gene 1 BRCA-1 or BRCA-2. While there is more understanding of how these genes work, repairing or replacing them (gene therapy) is not currently practical. Defects in ERB-2, whose product binds growth factors, accounts for 25% of cancers, and this defect can be monitored. Progress is especially being made in starving tumors by blocking angiogenesis, the development of new blood-supplying veins. Vascular endothelial growth factor (VEGF), which helps control angiogenesis, is in turn regulated by estrogen, so use of antiestrogens appears to retard cancer cell growth effectively.
Less progress but some hope on prostate cancer was offered by Ronald Morton, Sr., of the University of Texas at Houston. Rectal digital examination and the prostate specific antigen (PSA) assay are the best screening methods now available. But the former procedure misses many cancers, while the false positive rate of the PSA test continues to be of concern, causing many men to endure subsequent, unnecessary, and extensive examinations. Age-specific reference ranges for PSA values have been refined, while measuring the bound to free ratios seems to give more reliable results. When surgery is indicated, better techniques, including cryosurgical ablation, appear to result in fewer side effects.
Since prostate cancers often grow slowly, "watchful waiting" rather than intervention is still recommended, especially for patients over 65. In fact, in the question period, Dr. Morton indicated that the PSA assay is unnecessary for men over 70, since they would probably die of something else anyway.
Since plasma cholesterol levels also do not appear to be a risk factor in men over 70, presumably for the same reason, it is tempting to suppose that male septuagenarians have achieved a significant milestone. Nevertheless, at age 70, women are still ahead when adding up risk factors.
While the death rate from lung cancer is still the highest by far, John Minna of the University of Texas at Dallas presented the good news that 10 to 20 genetic mutations are required to trigger lung cancer. This probably explains why cigarette smokers don't succumb to the disease even more often than they now do. The bad news is that former smokers may be at higher risk than had previously been thought. Former smokers account for 50% of the lung cancer cases, and while the risk decreases with time, smokers who have quit for 40 years still retain genetic predictors for lung cancer. Dr. Minna stressed that this observation should reinforce efforts to discourage children and teenagers from ever smoking. The irony was noted that lung cancer causes death so quickly that there are too few survivors to form effective support/activist groups, as do breast cancer survivors, for example.
There have been some promising approaches to early detection based on genetic and antigenic changes in preneoplastic lesions. Advances in genetic epidemiology also have identified persons at increased risk of developing lung cancer. Therapeutic approaches have yet to produce a significant reduction in disease progression. The more promising lines of treatment include the anti-tubulin agents such as taxol; topoisomerase I inhibitors; anti-mitotic agents; and newer antimetabolites.
In line with the meeting's theme of the importance of genetics in cancer, the symposium "What Is the Role of Prophylactic Surgery in Breast and Ovarian Cancer?" discussed the dilemma women face when they are diagnosed with defective BRCA-1 or BRCA-2 genes. These women have an up to 80% chance of developing breast or ovarian cancer, and the question is whether they should elect to have bilateral mastectomy and/or oophorectomy.
William Wood, a surgeon at Emory University, outlined the pro argument while Judy Ellen Garber of the Dana-Farber Cancer Institute took the con position. The major arguments for the procedure were that it was 80% effective and that the majority of patients were satisfied with the result. The negative arguments stressed that (1) the operation involved extensive removal of tissue, (2) surgical skills varied for the operation and subsequent reconstruction, (3) women often have psychological problems with the procedure, and (4) animal studies indicate that long-term efficacy may not be as positive as is now believed.
The session took an unexpected turn when Dr. Wood, in response to a question from the chair, stated that, in reality, he never recommended prophylactic surgery for the breast because he believed that, with proper monitoring, breast cancer should no longer be considered seriously life-threatening. In response to further questioning following the meeting, Dr. Wood qualified his view by stating that his optimism for survival "applies only to treatment in 'ivory tower' settings where I always have been privileged to practice." He estimated that perhaps 50% or more of women facing this decision do not have access to the quality of care he is able to provide.
In any event, there was remarkable agreement (considering the recent mammography flap) among the speakers and the audience that providers should not recommend treatment but present the options for the patient as objectively as possible.
In regard to prophylactic oophorectomy, the success rate is only 50% because half of the cancers occur peritoneally. Nevertheless, women opt more for this procedure than for mastectomy because the psychological trauma is much less. The decision becomes even easier if the patient already has had children. Fortunately, onset of ovarian cancer related to the BRCA genes usually occurs later in a woman's child-bearing years.
Three areas of genetic disruption leading to cancer that received a good deal of attention were apoptosis, telomerase action, and angiogenesis.
Stanley Korsmeyer of Washington University in Saint Louis gave the Clowes Memorial Lecture about the BCL-2 gene family and its regulation of apoptosis. It represents a new oncogene category and a fresh area for genetic manipulation. When apoptosis is disrupted, cells tend to grow out of control.
The telomere-telomerase hypothesis represents a second potential mechanism for controlling cancer growth. Telomeres are lengths of DNA on the ends of chromosomes and become shorter as cells continue to divide. When they reach a critical length, the cell ceases to divide. The telomerase enzyme acts to lengthen telomeres and, since it is found mainly in cancer cells, it has become an important marker for cancer activity.
Promising results, using a new in situ hybridization assay that monitors telomerase RNA, were reported by Jerry Shay of the University of Texas Southwestern Medical Center at Dallas. Dr. Shay and colleagues demonstrated the usefulness of the assay in detecting pancreatic cancer, where 95% of pancreatic cancer specimens had the enzyme, while no enzyme was found in benign pancreatic tumor specimens.
A similar study on ascites or pelvic peritoneal washings in patients with ovarian carcinoma showed that 88% of the tumor patients were positive for telomerase activity, whereas only 2 of 42 control samples tested positive, and these were inflammatory cells.
The third control area emphasized at the meeting dealt with VEGF and angiogenesis. Studies by Michael Meyers of Louisiana State University with tamoxifen did not support the notion that VEGF was under estrogen control, although it was active at high doses. In a prostate cell line study by Joseph and Isaacs at Johns Hopkins University, androgen ablation coupled with Linomide, a quinoline compound, suppressed tumor growth by retarding angiogenesis by different mechanisms. The authors believe that the results merit further studies in humans.
Finally, preliminary results in diet studies were given special emphasis by AACR. Lycopene in tomatoes appears to help lung cancer patients (Li et al., Columbia University, Abstract #758); citrus lemonoids from lemons inhibit estrogen-receptor negative human breast cancer cell growth (Guthrie, Chambers and Carroll, Univ. of Western Ontario, Abstract #759); application of a green tea extract to skin protected against skin cancer in mice (Wang, Columbia University, Abstract #2455); and pasta had a protective effect in male rats against colon carcinogenesis as compared to ingestion of sucrose or glucose. I could embrace all these diets, especially pasta with tomatoes, and the tea extract as well if it were sold in a bottle.
Harry Brodie has been a principal investigator on NIH grants and contracts, and he supervised study sections at NIH in the Division of Research Grants for over fourteen years. He currently is a writer and also works on peer review projects in the Washington, D.C., area.
Endlinks
American Association for Cancer Research - Web site
includes a public education section on the negative impact
of cancer and the proportion of Federal tax dollars spent on cancer research and treatment,
as well as Congressional testimonies by Donald Coffey, the new AACR
president.
"Cancer War Needs Better Battle Plan"
by Judy Mann, The Washington Post, June 4, 1997 - discusses some of the concerns about
past and future strategies for dealing with cancer.
CancerNet - Web site from the U.S. National Cancer
Institute provides a broad range of current information on cancer research and treatment.
Reviewed by oncology experts, the site includes information for patients, health professionals,
and basic researchers.
Access Excellence - the periodical
from Genentech provides an excellent introduction to genetic testing, including testing for cancer genes.
a href="http://dna.botany.muohio.edu/GROUPE/groupe.htm">Gene Therapy in Oncology - an
instructive primer on the topic from Miami University of Ohio botany
department.
Genetic Odessy - the monthly publication from
the National Center for Genome Resources. The June issue includes an article on
genetics of colon cancer and a paper on genetic privacy.
Hereditary Colon Cancer Newsletter - from
the M.D. Anderson Medical Center. Directed at patients and the doctors who treat them.
American Institute for Cancer Research - Web site provides
current information on diet, nutrition, and cancer. Included at this site is information
for researchers on peer-reviewed funding by the organization, and a list of grant
recipients from the previous year.
a href="http://www.apopnet.com/">Apoptosis Online - keeps up with recent findings
in the field of programmed cell death, including findings relating to apoptosis and
cancer.
TAP Holdings, Inc. - Web site
with extensive and frequently updated information about angiogenesis in cancer.
Additional Web links of interest to cancer researchers may be found
at the end of the recent HMS Beagle meeting
brief covering breast cancer.
