By David N. Leff

The just-ending 20th century will go down in human history as an age of genocide and mass killing. Not that earlier centuries were guilt-free, but this one, people thought, would know better.

When it comes to deadly diseases, we do and we don¿t. Antibiotics made a good start at wiping out bacterial infections, but then their wanton overuse gave the bugs their drug-resistant comeback opportunity.

In industrialized countries, cancer deaths remain a massive statistic, second only to cardiovascular disease. And colorectal cancer mortality comes in second only to lung cancer. In 1996, 54,900 American men and women lost their lives to colorectal cancer, and 143,500 were diagnosed with the disease. More than half of those thus tardily diagnosed would be dead five years later. Early detection brings about a 90 percent five-year survival.

Diagnosis is the operative word. Gastroenterologists are acutely aware that catching a neoplasm of the colon in its early ¿ even precancerous ¿ stage can be lifesaving. Along that five-to-six-foot long digestive tube, precocious polyps are the first, still benign, stage of a tumor in the making. These adenomas projecting from the colon¿s inner wall signal their intent to go malignant by infrequent, subtle bleeding, as passing food particles abrade them.

Those hidden microscopic streaks of blood give physicians their first alert of a cancer in the patient¿s future. In many individuals that future is determined by their past. Five percent to 20 percent of colorectal cancer runs in families; the rest are sporadic. The American Cancer Society urges all average-risk people 50 years or older to undergo annual screening with a fecal occult blood test. More than 20 million of these do-it-yourself kits are prescribed each year in the U.S. They demand that for three days, the patient stick to a high-fiber, no-red-meat diet.

If the fecal occult test detects blood in the stool, this may be due to hemorrhoids or even a daily low-dose aspirin tablet to ward off heart disease. But the gastroenterologist takes no chances. An alternative screening supplement, sigmoidoscopy, explores the lower third of the colon via a flexible illuminated fiber-optic tube. It identifies only half of the polyps and cancers in the colorectal region, because of its limited reach. If either occult blood or sigmoidoscope is positive, a full-length, invasive, expensive and painful colonoscopy follows.

It¿s little wonder that most people shun these three inconvenient, humiliating procedures, so come to diagnosis only when the cancer has progressed to outright symptoms.

A biotech start-up firm, Exact Laboratories Inc. in Maynard, Mass., is working on a better way to diagnose colorectal cancer early and noninvasively, with ¿no-touch¿ self-sampling of stool by the patient. (See BioWorld Today, April 20, 1998, p. 1.)

Its method relies on the solid stool that traverses the colon from end to end ¿ conceptually, the body¿s own organic form of colonoscopy. The company¿s proprietary procedure got its first clinical trial on Wednesday at the 1999 Digestive Disease Week conference in Orlando, Fla. This annual event is co-sponsored by the four leading American gastrointestinal- and liver-disease associations.

Gastroenterologist David Ahlquist, who directs the Mayo Clinic¿s Colorectal Neoplasia Clinic in Rochester, Minn., reported to the Orlando meeting on his study of Exact¿s first-generation screening method. In the conference program it was titled: ¿To begin to evaluate whether a stool-based screening assay can accurately detect the molecular changes associated with colorectal cancers and colorectal adenomas (known as polyps).¿

Ahlquist selected 40 Mayo patients who each contributed a stool sample. ¿This group,¿ he told BioWorld Today, ¿comprised 21 established colon cancers, of whom the Exact test correctly detected 19, or 90 percent, compared to the conventional detection rates by fecal blood tests of 25 percent to 50 percent.

¿However,¿ he went on, ¿we did direct comparisons on the nine precancerous adenoma patients. The Exact test identified seven of the nine, or 78 percent, while fecal occult blood testing detected zero. And this result,¿ Ahlquist pointed out, ¿was statistically significant.¿

Exact¿s test correctly called all 10 (100 percent) of the subjects with no lesion as negative. ¿In this cohort,¿ Ahlquist recounted, ¿fecal occult blood testing also correctly called those negative, but the historical specificity of occult blood testing is 90 to 95 percent.

¿For a polyp to arise and eventually become a cancer,¿ Ahlquist explained, ¿requires a series of genetic alterations in the colon¿s epithelial cells. For sporadic ¿ not familial ¿ cancers, this progression is thought to take eight to 10 years, ample opportunity for clinical detection and intervention.¿

Molecular geneticists indict four human chromosomes ¿ 5, 12, 18 and 17 ¿ in the progression of colon epithelial-lining cells from normal to hyperproliferation to early adenoma to late adenoma to carcinoma to metastasis. Along these stations, each chromosome typically incurs mutation of an oncogene or a tumor suppressor gene ¿ APC, beta-catenin, K-ras, DCC and p53 ¿ which turns those cells malignant. (See BioWorld Today, April 2, 1999, p. 1.)

Finding Mutant Gene In Normal DNA Haystack

Exact¿s test identifies some of these genetic alterations in its stool assays. ¿We are developing a means for enumerating the alleles of specific genes,¿ Exact¿s founder and president, Stanley Lapidus, told BioWorld Today, ¿so that losses of heterozygosity can be identified with extreme accuracy.¿ He added, ¿Extracting a small amount of altered DNA from a sea¿ of normal DNA has required the development of several proprietary technologies.¿

Heterozygosity protects a person from cancer when their cells¿ chromosomes include a healthy gene from one parent along with a tumorigenic mutation of the other parent¿s gene. If the chromosome loses that non-mutated gene, the cell becomes homozygous ¿ and often cancerous.

The Mayo Clinic¿s Ahlquist is now recruiting 2,000 patients for a larger clinical study of the Exact screening system¿s accuracy. He is also organizing a 10-center, 5,000-patient trial to start next year. Meanwhile, Lapidus noted, ¿The company is still in the process of refining this test. We believe it will be available in approximately two or three years.¿

Diagnosis and treatment of colorectal cancer costs the U.S. economy approximately $7.5 billion annually. Early this month, Sen. Edward Kennedy (D-Mass.) introduced legislation proposing that private health-care insurers be required to cover colorectal cancer screening for the 69 million asymptomatic Americans age 50 and older. Since January 1998, the Balanced Budget Act has dictated that Medicare cover the cost of such testing. n