Genetic precision (ASCO annual meeting)

The trickle of discoveries that revolutionized cancer care is turning into a flood.

By Victoria Stagg Elliott — Posted July 21, 2008

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The increasing use of genetic profiling -- in regard to patients and their tumors -- is enabling physicians to identify more accurately who is most likely to benefit from certain treatment options, according to several studies and panel discussions at the June meeting of the American Society of Clinical Oncology in Chicago.

"We're on the cusp of an explosion of data that needs to be interpreted into future clinical trials and possibly into our treatment plans," said Neal J. Meropol, MD, who was part of a clinical science symposium on personalized medicine. He directs the gastrointestinal cancer program at Fox Chase Cancer Center in Philadelphia.

On the treatment front, researchers are identifying the genes expressed by various tumors that may determine drug response. Scientists from the University Hospital Gasthuisberg in Leuven, Belgium, presented data on how various forms of the KRAS gene in colon cancer tumors respond differently to the monoclonal antibody Erbitux. This drug, in combination with the FOLFIRI chemotherapy regimen, decreased the risk of disease progression by 32% in patients whose tumors expressed the gene's normal version but had no effect on those with the mutant form.

"This study helps us to identify which patients are most likely to benefit from adding the drug to treatment," said Dr. Eric Van Cutsem, lead author and a professor at University Hospital Gasthuisberg.

This paper was one of several dozen investigating the gene's impact. The hope is to save patients from the side effects of a drug that may not provide much benefit and ensure its expense is money well-spent.

"We are in an exciting era of targeted agents," said Julie Gralow, MD, chair of ASCO's communications panel. "We have hundreds more in the pipeline, but they're expensive. We need to know who will benefit and who won't. How we are going to afford these drugs is by better selection of patients."

Bottom line: The number of anti-cancer drugs has increased, and costs have skyrocketed. But survival has not always improved. A paper in the July 22, 2004, New England Journal of Medicine, for instance, reported that the regimen described cost $30,675 for eight weeks and advocated making deliberate decisions about when to use it. Depending on the type of cancer it is used to fight, the addition of Erbitux to an anti-cancer regimen increases survival by an average of six weeks to three months. Experts suspect the improved ability to choose those candidates most likely to get the maximum additional life expectancy will make it more worthwhile. It also may mean that health system resources will not be used to pay for pricey medications that won't have much of an effect.

Supportive care insights

Genetic testing also is starting to make inroads in the supportive care arena and may lead to more effective use of erythropoietin, a controversial drug commonly used to treat chemotherapy-related anemia. The Food and Drug Administration added warnings to the label last year in response to data suggesting that this medication accelerated tumor growth and increased the risk of mortality. A study presented at this meeting found that whether a tumor grew in response to this drug depended on the amount of erythropoietin receptor messenger RNA it produces. "This may mean we can use erythropoiesis-stimulating agents in a targeted way," said Dr. Gralow, also associate professor of medicine at the University of Washington, Seattle.

Another study suggested that, for lung cancer patients, the existence of cytokine gene polymorphisms could determine the amount of pain and the effect of analgesics. A second paper presented at the same session documented the genetic differences that may increase the risk for venous thromboembolism.

"It's an exciting time in oncology. There's so many new drugs to treat the cancer, but there's more to treating the cancer than just shrinking the tumor," said Howard L. McLeod, PharmD, the official commentator on both papers after their presentation at a clinical science session. He directs the Institute of Pharmacogenomics and Individualized Therapy at the University of North Carolina, Chapel Hill. "These studies are a nice start."

Determining relevance

But while genetics is now a more important part of cancer care, questions are being asked about the relevance of testing for one of the more established markers. Data presented at last year's meeting noted that some patients with HER2-negative breast cancers could benefit from the same treatment given to those who test positive for this gene, thereby indicating that the answer may not be relevant. Experts said the evidence was not yet strong enough to end regular use of this kind of genetic assessment and that the findings may have more to do with inaccurate testing than a lack of influence of this gene.

"The presentations from a year ago left a lot of confusion but emphasized the importance of high-quality HER2 testing," said Dr. Antonio C. Wolff, who chaired the educational session, "HER2-Targeted Therapy: Why Bother Testing?" He is also associate professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore.

Concerns also are being raised about the amount of research funding. The American Medical Association promotes appropriate use of pharmacogenomics in drug development and clinical trials. But many experts worry that flat funding of the National Institutes of Health since 2004 is slowing the transition of novel gene science from the bench to doctors and patients.

"We have a growing backlog of genetic discoveries that are waiting to be turned into targeted therapies," said ASCO Immediate Past President Nancy E. Davidson, MD. "Progress against cancer requires a consistent commitment over time, and research is the best tool we have to fight the battle against cancer."

Adjusted for inflation in the Biomedical Research and Development Price Index, NIH's budget has declined 13%. The National Cancer Institute's budget has gone down by 12%.

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Lung cancer mortality rates prove stubborn

Experts say strategies to screen, detect and prevent lung cancer are desperately needed because while overall cancer mortality has declined significantly, the numbers related to this form of the disease have not. Here is how lung cancer mortality compares to overall cancer mortality from 1975 to 2005. Rates are per 100,000 and age-adjusted.

Mortality rates
All cancers Cancer of the
lung and bronchus
1975 199.1380 42.5569
1976 202.3006 44.1964
1977 203.0183 45.4863
1978 204.4228 46.8791
1979 204.5274 47.6864
1980 206.9564 49.4138
1981 206.3952 49.9855
1982 208.3193 51.4301
1983 209.2084 52.4015
1984 210.9059 53.3595
1985 211.3468 54.3203
1986 211.7853 55.0351
1987 211.9130 56.2432
1988 212.6221 56.9729
1989 214.3027 57.8970
1990 214.9473 58.8538
1991 215.0639 58.9927
1992 213.4576 58.9014
1993 213.4463 59.1275
1994 211.7413 58.5421
1995 209.8861 58.3841
1996 206.9976 57.9074
1997 203.5534 57.5061
1998 200.8236 57.0761
1999 200.7218 55.4161
2000 198.6903 55.8420
2001 195.8747 55.2971
2002 193.6679 54.9638
2003 190.0022 54.1459
2004 185.8440 53.3212
2005 184.0096 52.7824

Source: National Cancer Institute's Surveillance Epidemiology and End Results database

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Lung cancer: Focus on screening, prevention

With lung cancer accounting for approximately 29% of all cancer-related deaths and failing to mimic the downward trend of the overall cancer mortality rate, scientists are exploring new ways to detect it early, when it is most treatable. They also are testing drugs that may prevent it, according to several expert panels and studies presented at the American Society of Clinical Oncology annual meeting in Chicago last month.

"Survival is very poor and this has improved very little in the past 25 years. There's certainly a need," said James Jett, MD, professor of medicine at the Mayo Clinic College of Medicine in Rochester, Minn. He is involved in several early-detection trials.

Screening is the area with the most science but also the most controversy. Various scanning modalities, as well as sputum cytology, have been tried but are not widely used for screening because they have not been shown to improve overall mortality. False-negative and false-positive rates have been high, although one study suggested that a protocol incorporating spiral computed tomography with watchful waiting could overcome this issue.

Researchers randomized 30,047 former and current smokers ages 50 to 74 to receive either usual care or annual CT screening. Of this group, 7,556 have had baseline scans, and preliminary data indicated that monitoring the nodules detected in that procedure and responding if they grew led to fewer patients undergoing surgical workups for growths likely to be benign. Additionally, a number of cancers that otherwise would not have been found were detected early.

"Low-dose CT scanning for lung cancer is promising," said Dr. Rob J. van Klaveren, lead author and a pulmonary oncologist at the University Hospital in Rotterdam, the Netherlands.

This study is expected to be completed by 2009 with mortality data available in 2015.

Research also is being conducted to track bloodborne biomarkers that may indicate the presence of cancer in the lung. Investigators from the University of Cologne in Germany presented data on an RNA pattern identified by comparing blood samples taken from smokers with lung cancer to samples from healthy controls. Preliminary findings suggest this work could lead to a blood test that would identify those who have lung cancer or are likely to develop it within two years.

Researchers are investigating possible uses of pharmaceuticals in regard to prevention. According to one study, 400 mg of the Cox-2 inhibitor celecoxib twice daily reduced a marker of cell proliferation in the lungs.

"We cannot say that taking celecoxib will prevent lung cancer, but it was safe to administer. We did not have any cardiac events. We need to move forward with perspective validation studies," said Edward S. Kim, MD, lead author and assistant professor of thoracic head and neck medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston.

Previous studies of these drugs as preventives for colorectal cancer were derailed when cardiovascular risks became apparent. Those researching their use for lung cancer prevention say the benefits may outweigh the risks in this situation. The key difference is that screening for colorectal cancer is widely available. The same cannot be said for lung cancer.

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Research findings: Alleviating fatigue, treating testicular cancer, cutting risks of recurrence

A stimulant may address the severe fatigue affecting many cancer patients, according to a study presented in June at the American Society of Clinical Oncology annual meeting in Chicago.

Researchers analyzed data on 642 patients randomized to receive 200 mg of modafinil or a placebo. Those with severe fatigue were most likely to benefit from the drug, while those with mild or moderate symptoms did not. The drug, which has Food and Drug Administration approval for the treatment of narcolepsy, was supplied by manufacturer Cephalon Inc., with study funding from the National Cancer Institute.

Cancer patients often struggle with fatigue long after treatment ends. The authors hope modafinil will reduce the risk of the problem becoming lifelong.

"One would hope that if you get it early and treat it successfully, then it won't occur later," said Gary R. Morrow, PhD, lead author and director of the University of Rochester Cancer Center Community Clinical Oncology Research Base in New York.

Scientists also are fine-tuning cancer treatments to minimize long-term adverse events or to suit patient preferences. One study found a single dose of chemotherapy could be as effective as radiation, and less toxic, in treating early-stage testicular cancer.

Researchers from several European nations, South Africa, Canada and Brazil randomized 1,477 patients to receive one dose of carboplatin or two to three weeks of radiation. After an average of 6.5 years of follow-up, both study arms had similar relapse-free survival rates, but the men who received the drug were less likely to develop cancer in the previously unaffected testicle.

Other papers looked at strategies to reduce the risk of recurrence. For instance, Austrian Breast and Colorectal Cancer Study Group researchers randomized 1,801 premenopausal women treated for hormone-receptor positive breast cancer to various forms of ovarian suppression, with or without zoledronic acid. After five years, the drug was shown to reduce the risk of relapse by 35%, although there was no statistically significant difference in overall survival.

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External links

Information about lectures, presentations and other developments at the American Society of Clinical Oncology annual meeting 2008 (link)

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