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The author's parents, Martha and Marshall Ledger, dressed to tango.



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The lab announced the discovery of a very subtle genetic weakness– tucked in an otherwise intact DNA sequence.



Through various misguided genetic signals, a person’s colon lining finally falters
in the normal, three-day
pattern of generating and replacing cells.



In cryosurgery, Choti burrows a pencil-thick probe into the core of a liver tumor and freezes it.
 
 
 
 
 
 


Vogelstein & trainee
Vogelstein reviews data with
one of his many trainees.


Medical oncologist Louise Grochow.
Too few drugs exist for colon cancer, says medical oncologist Louise Grochow.



Surgeon Michael Choti
Surgeon Michael Choti focuses on the liver where colon cancers often metastasize.

Colon Cancer Conversations

By Kate Ledger

As Bert Vogelstein’s world-famous laboratory unveils the genetics of colorectal tumors, American families are learning they’re at risk.

  F
or the last few years, in visits home to the cozy, turn-of-the-century house in West Philadelphia where I grew up, dinner table conversations with my parents often have crept to one particular topic. My mother's usually the one who broaches it. "It might not be such a bad idea for you," she'll say gently, "to be gene tested." She has good reason to suggest that my younger brother and I take a simple blood test to check for a certain genetic peculiarity. We're concerned about colon cancer. I was a sophomore in college in 1989, and my father was not quite 50, when the pronouncement of cancer dropped anchor in our lives. My father battled through surgery. The doctors found malignant cells in his lymph nodes. During six months of chemotherapy, his skin was sallow; he was exhausted; he threw up. The taste of food, he reported wryly, was ruined by the metallic taste the drugs left in his mouth. For an entire year, my mother kept watch on the color in his face, as if a normal hue in his cheeks would reveal his health returning. In his style, he rarely talked about being sick and barely missed a day of work, but even today as I write, my eyes well with tears remembering how scared we were. Now, eight and a half years later, we consider ourselves lucky. His annual checkups show no sign of the ordeal. "A blip on the screen of my life," he called the cancer recently, before heading out the door with my mother for their newly found passion, Argentine tango.

Not everyone is so fortunate. One hundred thirty-five thousand Americans will be diagnosed this year with colorectal cancer; 55,000 will die from it. Ever since our father's diagnosis, my brother and I have been well aware that, with a close relative who's had the disease, we have a greater chance than the general population of eventually turning up with colon cancer ourselves.

The discoveries leading the world to understand that a predisposition to colon cancer can run in a family have unfolded one by one in the internationally famous molecular biology lab of Bert Vogelstein, M.D., and Kenneth Kinzler, Ph.D. Vogelstein ranks today as the preeminent scientist in the world, according to a list published by the Institute for Scientific Information in Philadelphia. ISI counted footnotes to pinpoint which scientific papers were cited most often by other scientists. With 22 high-impact publications, Vogelstein stood far above the group. Second came Kinzler.

The two share a lab on a corner of Hopkins' East Baltimore campus in a squat, brick building that was once a supermarket. As one component of a research-oriented Bowel Tumor Working Group, this is where colon cancer first was characterized in the early 1980s as a condition involving mishaps in specific oncogenes and tumor suppressor genes. Ten years later, researchers in the lab pinpointed the culprits for two inheritable colon cancers: one that leads to the rare familial adenomatous polyposis (FAP), in which teen-agers grow hundreds of polyps that turn cancerous by the time they reach the age of 40, and the other leading to hereditary nonpolyposis colorectal cancer (HNPCC), which accounts for a sizeable 2 to 4 percent of all familial cases.

Last August, the lab announced another groundbreaker: the discovery of a very subtle genetic weaknessan innocent-looking misspelling tucked in an otherwise intact DNA sequencethat makes a whole ripple of colon cancer-causing mutations more likely to roll into motion. In addition to identifying the problem, the lab reported in Nature Genetics that the mutation appears in as many as 6 percent of European- descendant, or Ashkenazi, Jews. Suddenly it's clear that, for a slice of the American population, gene tests will be the best first step in watching out for colorectal cancer.

For my family, Jewish, with ancestors who hailed from tiny Russian towns, the latest development has added new weight to the dinnertime discussions. The potential benefits of a genetic test seem obvious: If my brother and I test positive for  this mutation, we'll have a better idea of how soon and how often to be examined by colonoscopy for the appearance of polyps. With vigilant screenings, we might be able to evade cancer entirely.

At the same time, we're stalling. It's a sobering undertaking, after all, to begin probing the body's makeup for harbingers of the future.

Frenzy for Information

Apparently, my family is not the only one with ears perked for news regarding colon cancer. In the first six weeks after the Vogelstein/Kinzler lab announced the latest discovery to the press, more than 1,200 people phoned Hopkins from around the country to learn more about the gene test that the lab developed to make immediate use of the new information. (The test is currently available through Hopkins' pathology department.) Some callers were Ashkenazi Jews, concerned that they might be among the 400,000 nationwide carrying the gene; others were physicians calling on behalf of Jewish patients with family histories of colon cancer. Some physicians wanted to take the gene test themselves.

The frenzy for information is similar to the one that broke in 1993 when the Vogelstein/Kinzler lab unveiled the HNPCC gene, the first ever linked to a fairly common colon cancer. Today, as five years ago, Hopkins is asking people who want predictive testing to undergo genetic counseling first. One of the counselors who's fielded hundreds of calls told me the warnings she offers patients, and what she would tell me if I went for counseling: A positive test for the recently discovered mutation doesn't necessarily mean that my brother and I will get cancer. The mutation simply pr  edisposes people to further mutations that may or may not occur in the normal dividing and aging of cells. At the same time, not  having it is no guarantee that colon cancer wouldn'tspring through some alternative genetic pathway.

The fact is that in the majority of colon cancer cases, inheritance probably plays no part. As many as 80 percent of tumors strike people with no family history, the result of an unlucky lifetime accumulation of genetic errors pushed over the edge by diets heavy in fat and low in fiber and lifestyle choices like smoking. The disease occurs overwhelmingly in affluent countries, predominantly in people over the age of 60. Through various misguided genetic signals, a person's colon lining finally falters in the normal, three-day pattern of generating and replacing cells. Two mistakes occur: Immature cells, those about to differentiate into epithelial cells, begin to proliferate out of control, and, just as the mature cells complete their life cycle, they refuse to die the programmed cell death called apoptosis.    Soon, a rippling, budding mass pokes into the interior of the colon in the form of a polyp.

In nine out of 10 people, this mishap never becomes dangerous. In the other 10 percent, the protuberance continues to undergo genetic changes. The cells turn malignant and burrow into the underlying submucosal tissue where they find blood vessels that can transport them to lymph nodes and to other organs, usually the liver and the lungs. Once colon cancer spreads, it's very difficult to cure.

With many cancers, a look at the malignant cells under the microscope helps physicians gauge the disease and fashion treatment. Not so with colorectal tumors, says pathologist Stan Hamilton, M.D., who as one of the original members of the Bowel Tumor Working Group gained national recognition when he identified a number of the variations of heritable polyposis syndromes. Eighty percent of colorectal tumors look pretty much the same: They're moderately differentiated, with cells that look something like those in the normal epithelium, but display enlarged nuclei, abundant DNA and a defective mucus-producing system. For years, the behavior of these cells has stumped pathologists. In fact, since 1932, the same, modestly revised system, Dukes' classification, has been the authoritative method to determine whether or not a tumor will kill a patient. This failure to discover new diagnostic subtleties is nothing short of frustrating, Hamilton says; physicians can't yet predict with a high degree of accuracy how the disease will progress. "It would help to know more about the tumor," he acknowledges, "to be able to say, 'Yes, this is a tumor with a high likelihood to be aggressive, so it's worth it to risk the possible complications of extensive surgery and chemotherapy' or, 'No, this is a low-risk tumor and we don't want to cause more harm than good.'"

At this point, physicians can only offer patients educated guesses about their odds for surviving. When my father began chemotherapy, doctors told him the drug combination would give him a 70/30 chance of beating the disease. How do you make sense of 70/30 oddsare they tipped quite enough in your favor? Is 30 percent too much room for failure especially when what's at stake is your dad?

The most poignant part of the whole colorectal cancer story, however, is that, unlike most other cancers, this disease is preventable. Polyps develop slowly and may take 10 to 20 years to convert to a full-fledged malignancy. Usually they're visible during colonoscopy (only rarely, Hamilton says, are they flat and hard to see) and with one simple snip can be removed before they become dangerous. But amazingly enough, colon cancer ranks as a killer in the United States second only to tobacco-related lung cancer. Screening for polyps is expensive, and Americans, it seems, don't concern themselves with colorectal cancer, as many men now do with prostate cancer and women with breast cancer. In fact, until Baltimore Oriole outfielder Eric Davis intermingled his chemotherapy sessions with playing in last fall's American League Championship Series, who ever heard much in the press, or even in public, about this often-deadly disease?

Taking on the Tumor

Talk to surgeon/oncologist Michael Choti, M.D., and he'll tell you right off that removing the tumor's the only sure-fire route to a cure. With the establishment last year of the Colon Cancer Center that he directs, discoveries made by Hopkins researchers are finding their way more smoothly back to patients. Meanwhile in the operating room, new approaches and surgical techniques are heightening the outcomes of resections of the colon and rectum and giving patients a wider range of possible treatments. Many medical centers, Choti says, jump straight to surgery, leaving patients who have tumors in the lower rectum no alternative but a colostomy, an operation that refashions the remaining intestine so that the body's waste empties into an externally worn bag. (My father didn't need one, but we all agreed it was another onerous threat that added to our worries about his surgery.)

One new path is a presurgical course of chemotherapy and radiation therapy when the tumor is in the rectum, shrinking the tumor and making the resection less likely to venture near nerves that control sphincters or sexual functions.In a few startling cases, this treatment has actually obliterated rectal tumors altogether so that there was nothing for the surgeon but telltale scar tissue and no signs of the cancer microscopically. Another innovation that's improved surgery is transrectal ultrasonography, which allows surgeons to assess the size and shape of the tumor before treatment begins.

When colorectal tumors metastasize, they often take root in the liver. Choti has focused much of his attention on perfecting liver resections to excise the early metastatic signs of the disease. The surgeries can be long, complicated and, in patients whose cancer has spread to the lungs, they require the handiwork of a thoracic surgeon. Choti also now uses another tumor-destroying method called cryosurgery, burrowing a pencil-thick probe into the core of a liver tumor and freezing it. "For patients who have multiple tumors that can't be removed by resection or who have a medical condition that makes resection impossible, cryosurgery may be an option," he says. "What's not clear yet is whether this method is ultimately going to be as effective as cutting the tumor out."

But getting rid of the visible mass can be only the beginning of eradicating the cancer from the body. By far the greatest challenge is tailoring chemotherapy to destroy lingering  malignant cells. Because the colon is a polluted environment, its cells are unusually efficient at expunging toxins. This characteristic makes it more difficult for cancer-fighting drugs to permeate the tumor and do their work. For more than 20 years, says medical oncologist Louise Grochow, M.D., a Colon Cancer Center member who also leads Hopkins' drug development group, the mainstay drug for colon cancer has been 5-Flurouracil, or 5-FU, which interferes with DNA replication in the cancerous cells. Recently, after years of tinkering with dosages of this substance, physicians have finally begun to learn how to use it more effectively and with minimal side effects.

This was the drug that my father took in intravenous spells for six months, the one that saved his life. A new enhancement to 5-FU that thrills Grochow adds ethynyl uracil, which blocks the enzyme dihydropyrimidine dehydrogenase and prevents 5-FU from being broken down. With longer endurance in the body, oral doses may replace the long-familiar, cumbersome intravenous catheter. The combination passed the phase I trials for toxicity, and Grochow is now monitoring its effectiveness and adjusting the scheduling as it's tested in the phase II stage.

Just last year, Hopkins led industry-sponsored trials to gain U.S. approval for a second drug, cpt-11, or Camptosar, which became the first new pharmaceutical approved for colon cancer in 30 years. Camptosar forces the DNA unwinding enzyme, topoisomerase, to glom onto supercoiled strands of DNA. Instead of unravelling the genetic material, the enzyme gums up the twisting nucleic ribbons and the DNA eventually snaps. It's the only drug approved for use when 5-FU fails.

Grochow also is excited about a new line of drugs, just entering phase I trials at Hopkins, that take a completely different tack. Instead of interfering directly with the cancerous cells, the class of nine or 10 drugs focuses on inhibiting the cell-mediating cytokines that encourage nourishing blood vessels to grow toward the tumor. Without the nutrition from the blood vessels, the innermost cells of the tumor die, leaving a tiny, quiescent bundle. Patients may need to take the medication daily for life in order to keep the tumor in check (a financially enticing opportunity for drug companies, the oncologist points out, which may push the development of effective medications more quickly). Some of the drugs already have been tested at Hopkins in treating brain tumors, and in the near future, Grochow hopes, will soon be ready for phase II trials in colon cancer. "One of the reasons I stay active in this field," she states firmly, "is that I don't want to have the same few drugs to use next year that I do now."

Falling Death Rates

The good news in colon cancer, pathologist Hamilton tells me, is that the death rate in women has dropped during the last three decades, and it's finally on a downward trend in men. "You can't point to any one reason," he says. "Changes in dietary factors, earlier detection, dedicated surgeons, adjuvant therapyit's the whole package." There's also hope in the form of chemoprevention for people who have inherited the rare mutation for FAP, the condition that causes hundreds of pre-cancerous polyps and usually requires prophylactic removal of the entire colon. In 1993, gastroenterologist Frank Giardiello, M.D., whose work spans the Bowel Tumor Group and the Colon Cancer Center, tested a non-steroidal anti-inflammatory drug called sulindac in FAP patients and found their polyps often disappeared completely. He's currently investigating other non-steroidal drugs that won't have sulindac's stomach-upsetting side effects.

Pushing many of these projects forward is funding from an eight-year gastrointestinal SPORE grant (the acronym stands for Specialized Program of Research Excellence), aimed specifically at translating the lab discoveries into patient care. The prestigious grant (one of two in gastrointestinal cancers the National Cancer Institute has awarded across the country; Hopkins also has SPORE grants to study cancers of the prostate and lungs) of nearly $2.5 million a year backs a list of studies ranging from finding the molecular markers for metastatic disease to improving detection of colorectal cancer. It also supports the steadily growing tissue repositories and the family registrybegun 25 years ago by Hopkins' recent Lasker Award winner, Victor McKusick, M.D., and now directed by Giardiellowhich tracks cancer in more than 2,000 families and stands as one of the largest of its kind in the country.

For me and my brother, the question of whether to be gene tested remains on hold. We talk about the overhanging hazard of being discriminated against by insurance companies if we find we have a "pre-existing condition." We also speculate how having the information might benefit us, perhaps inspiring us to eat more healthfully or undergo regular screening for polyps. "It's impossible to avoid the superstitious thinking," my brother observes wisely, "that once you let someone check you out for a disease, you'll suddenly have it."

One member of the Colon Cancer Center, genetic epidemiologist Gloria Petersen, Ph.D., is studying just that: what she calls "the whole psychological work-up" of people who decide to go ahead with gene testinghow they feel when they discover that they do or don't carry the mutation, why they want the information in the first place, and finally, their expectations for their futures once they find they carry the colon cancer gene. "It's a story that's going to evolve over the next several years," she forecasts.

My brother and I will be listening.*


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