By Monica Zangwill, MD

Ten years ago when doctors gave Gabriel Bassan‚ now 41‚ a five-year survival rate of 40% for his diagnosis of ALL (acute lymphoblastic leukemia)‚ he felt it was a difficult number.

“When someone tells you your chances of surviving are about 50-50‚ that’s a pretty cold slap in the face‚” he says. So instead Bassan focused on the short-term numbers‚ like his 80% chance of getting into remission. Now cancer-free‚ he says‚ “I knew enough about science and medicine to understand there aren’t any fixed numbers.”

Fixed numbers are hard to come by in medicine‚ especially cancer medicine. But since the sequencing of the human genome—the entire map of hereditary genetic material within a human cell—in 2000‚ cancer researchers are optimistic about new gene-analyzing techniques that provide greater accuracy in diagnosis‚ prognosis‚ and therapy of many cancers.

Genomics & Cancer
Cancer specialists have always postulated that genetic change is a key to understanding how cancer starts‚ how it progresses‚ and how it can be stopped. Since 2000‚ the field of genomics‚ the study of all our genes‚ and research into the origins of cancer have swiftly dovetailed. Currently‚ cancer researchers have seized hold of gene-analyzing techniques and are using them to examine cancer cells down to their inner sanctum—the individual genes and DNA that regulate their activity. At the forefront of this research is a fast method to analyze genes in a cell‚ called gene profiling.

Using a specific laboratory technique that plates out genes onto a glass slide called a microarray or “gene chip‚” scientists can scan through thousands of genes simultaneously looking for patterns and differences in expression between cancer cells and normal cells. The result is an extensive pattern‚ or gene profile‚ of which genes are active in any cell. The amount of information gleaned and the amount of time saved looking for abnormal genes that might be involved in cancer-causing mechanisms is enormous‚ says Charles Perou‚ PhD‚ assistant professor of genetics at the Lineberger Comprehensive Cancer Center at the University of North Carolina‚ Chapel Hill.

“In the past‚” he says‚ “you had to go on a one-by-one basis and ask‚ ‘Is this gene different between tumor and normal? Is the next gene different?’ Now in the same amount of time that we could previously ask if one gene is different‚ we can ask whether 30‚000 genes are different.”

Using these gene profiles to better understand cancer biology—how cancers develop and work‚ how they respond to treatment‚ and which genes could make better targets for therapy—is the rallying call of the genomics researchers.

Better Diagnoses and Prognoses
The first use of gene profiles has been to identify and classify tumors in a whole new way. For example‚ scientists at the National Cancer Institute (NCI)‚ Bethesda‚ Maryland‚ recently used gene profiling to help shed light on a long-standing clinical conundrum of lymphoma diagnosis‚ which typically involves an extensive classification system dependent upon what the tumor looks like under the microscope.

But patients with the same lymphoma classification from microscopic diagnosis often fare very differently—some surviving cancer-free‚ many succumbing no matter what treatment is given. Using gene profiling to look at these lymphoma cells‚ scientists at the NCI found that although these lymphoma tumors look the same under the microscope‚ their gene activity on gene chips is very different.

“It’s different diseases that can be identified with profiling‚” says Louis Staudt‚ MD‚ PhD‚ senior investigator at the Center for Cancer Research at the NCI.
Next Dr. Staudt and colleagues found that from the gene profiles alone‚ they could predict the patients who had a 70% survival after chemotherapy versus those with only a 15% survival.

In other words‚ the gene profiles determined distinct diseases in identical-looking cells and could pinpoint prognoses much better than the microscopic diagnoses.

Similarly‚ Dr. Perou’s research in gene profiling found that a particular type of breast cancer‚ infiltrating ductal carcinoma‚ is not one disease but probably three or four diseases that arise from different cell types.

“We need to understand the distinctions and treat patients based upon these differences‚” explains Dr. Perou‚ “as opposed to what we were doing in the past when we were treating patients all the same and then observing that some responded and others didn’t.”

With gene profiles delineating the difference between tumors‚ researchers can now gain understanding into why some patients respond to treatment and others don’t‚ says Dr. Perou.

Matching Treatment to Tumor
Using gene chips‚ scientists hope to not only improve diagnoses and prognosis estimates but also to better predict how tumors will act. Sridhar Ramaswamy‚ MD‚ an oncologist at the Dana-Farber Cancer Institute and the Whitehead Institute Center for Genome Research in Cambridge‚ Massachusetts‚ performs gene profiling studies in his lab on many cancer types.

“In the research setting‚” he says‚ “it’s possible to take on tumors which are identical by classical criteria and really tell them apart on the basis of their gene expression profile and show that those differences matter in terms of overall patient survival or the propensity to develop metastases.”

Dr. Ramaswamy expects the next step in gene profiling will be determining which tumors are sensitive to which types of chemotherapy. Then patients will be better matched to treatments proven to work with their specific tumor.

For someone like Jeanne Cooper‚ 44‚ of Newton‚ Massachusetts‚ who was diagnosed with a rare cancerous carcinoid tumor‚ information about gene profiling could make a world of difference. Because her tumor cells were so unusual‚ her doctors didn’t know if the cancer would recur. Cooper says her doctors advised her‚ “They said‚ ‘Yeah‚ you ought to do chemotherapy. You could not do it‚ but you ought to do it because we don’t know what’s going to happen.’” So Cooper opted for the chemotherapy‚ but felt sick after every treatment. “In this kind of case‚ [gene profiling] probably would be helpful‚” she says.

However‚ matching treatment to specific cancers in clinical patients based on gene profiling for tumors such as Cooper’s is in its infancy.

Looking for New Targets
Ultimately‚ researchers hope to use gene profiling to find new targets for cancer therapies. Once the gene chip determines the activity patterns of thousands of genes‚ says Dr. Ramaswamy‚ you can start to look for what is called a gene signature—a set of genes or relationships between genes that might be important in initiating cancer. “For example‚ when gene A goes up‚ gene B goes up‚” says Dr. Ramaswamy. After figuring out what a gene signature does‚ it can be a prime target for chemotherapeutic drugs.

Dr. Staudt’s research group at the NCI is starting to focus on these gene signature targets. They found a gene signature within the gene chip for lymphoma that codes for a cancer-causing signal. It’s as if this gene signature allows the cell to continue multiplying forever. In the laboratory‚ Dr. Staudt says‚ the lymphoma cannot survive without this gene signature.

“When we inhibited it experimentally‚” Dr. Staudt says‚ “we killed those cells.” Based on this work‚ the NCI will soon start a clinical trial with a drug to block the signal from this gene signature‚ which is expected to be effective in patients whose tumors carry this gene signature.

A Shining Future
It is work like Dr. Staudt’s at the NCI that has many cancer specialists very excited about gene profiling. However‚ cancer scientists are quick to point out that results in the clinical setting are still a long way off.

“The only way to show that these things work [with patients] is in large prospective clinical trials‚” says Dr. Perou. “And a lot of times you need five years of follow-up before you get the answer you need‚ which will then be used to guide therapy. But every human tumor type is getting profiled as we speak—breast‚ lung‚ lymphoma‚ leukemia‚ brain tumors‚ liver‚ kidney‚ prostate—all of those and more.”

Dr. Ramaswamy agrees. “I think we need to cover some ground before we can offer genetic profiling of a person’s tumor as part of standard care‚” he says. “But that’s definitely where the field is moving.”

Genomics has opened up a huge window into the complexity of how cancer works and cancer specialists are working feverishly to understand that complexity and integrate it into helping patients.

Indeed‚ researchers reported in The New England Journal of Medicine in the December 2002 issue about the ability to predict breast cancer’s propensity to metastasize based on DNA microarray analysis. Using the 70 genes they had earlier identified as a gene-expression signature that provided a good indicator of breast cancer survival‚ researchers examined frozen tumor tissue from 295 women under age 53 who had been diagnosed with primary breast cancer. The women were classified as having either a good prognosis or a poor one. All had been diagnosed with early-stage cancers; 151 were node-negative‚ 144 node-positive.

Using DNA microarray analysis‚ the investigators found 180 of the women had a poor-prognosis signature‚ while 115 had a good-prognosis signature. Subsequent overall 10-year survival rates were about 95% and 55%‚ respectively. The profile performed best as a predictor of early distant metastasis‚ and the method outperformed conventional prognostic criteria.

Investigators concluded that a tumor’s ability to metastasize is an inherent genetic property‚ independent of regional spread through lymph nodes. Their findings may be a useful tool in guiding adjuvant therapy for patients with lymph-node involvement and could reduce both overtreatment and undertreatment by identifying patients who would benefit from adjuvant systemic treatment.

In late January 2003‚ gene profiling moved one step closer to clinical application when Roche pharmaceuticals announced it was partnering with Affymetrix‚ Inc.‚ by licensing its patented GeneChip® technology to explore the development of diagnostic products for a wide range of diseases‚ one of which is cancer.

Gene profiling appears to be another breakthrough into elucidating the mechanisms of cancer. Dr. Perou says it’s like searching in the dark and then someone turns on the light.

For patients like Bassan‚ who relied on prognostic numbers‚ or Cooper‚ who would like more information on the potential activity of her tumor‚ gene profiling could add tremendously to their level of comfort and understanding of their disease. Patients and physicians alike hope the lights continue to shine brightly on the progress of gene profiling.