Bittersweet Gene

Predicting drug response in colorectal cancer.

On Easter Sunday in 2007, Doris Banks awoke from a nap with excruciating abdominal pain. Suspecting a burst appendix, she and her husband rushed to the emergency room. Her suspicion was confirmed, and Banks had an emergency appendectomy. But her surgery revealed something far more sinister than a ruptured appendix—Banks had colorectal cancer that had spread to her abdomen. The surgeon removed a large section of her colon and several lymph nodes along with her appendix.

Banks’ initial reaction was shock. “I had probably only missed five or six working days in my life,” she says. “I was just one of the healthiest people you would ever meet.”

Banks, a 53-year-old salon owner from North Carolina, was diagnosed with metastatic colon cancer; tests showed the cancer had spread to her liver. Over the next year, Banks received multiple rounds of chemotherapy and had a large portion of her liver removed.

After recovering from liver surgery, Banks faced more bad news. A CT scan in early 2008 revealed the cancer had continued to spread. “At that point, I was extremely discouraged,” recalls Banks, who had hoped the liver resection would remove the last of the cancer. “In your mind you think, ‘OK, this is going to get it, and then I’ll be on my way.’ ”

With standard treatment failing, Banks’ oncologist, Richard Goldberg, MD, director of oncology at the Lineberger Comprehensive Cancer Center at the University of North Carolina, considered putting Banks on a new cancer-fighting drug. But first he wanted to test her tumor for mutations in a gene known as KRAS, which, if positive, could mean she would have little chance of benefiting from the drug.

The drug Goldberg had in mind was Erbitux (cetuximab), which belongs to a growing family of targeted therapies that are changing the way doctors approach cancer treatment. By studying each patient’s tumor to determine which biological pathways have gone awry, oncologists can use targeted drugs to hone in on precisely those pathways. This tumor characterization strategy will also help doctors to pinpoint which patients are most likely—or least likely—to benefit from a given drug.

Erbitux and a related drug called Vectibix (panitumumab) both block a protein called EGFR (epidermal growth factor receptor), which promotes the growth and survival of tumor cells and is often expressed at high levels on colorectal tumors.

In patients such as Banks who have advanced disease and do not respond to standard chemotherapy, Vectibix and Erbitux can be beneficial. Recent studies have shown that both drugs, given alone or in combination with standard chemotherapy, can improve response rates and progression-free survival in these patients. Despite the benefit of these drugs, however, the five-year survival rate for patients with stage 4 disease still hovers at a discouraging 5 to 10 percent.

The likelihood of benefiting from EGFR inhibitors is not equal among all patients. Erbitux and Vectibix were initially approved in 2004 and 2006, respectively, for the roughly 75 percent of colorectal cancer patients whose tumors express EGFR. And, in some studies, higher than normal expression of the receptor was linked to an even better response.

Although it made sense at the time to assume that only EGFR-expressing cancers would respond to EGFR inhibitors, this logic hasn’t held up, says Wells Messersmith, MD, director of the Gastrointestinal Medical Oncology Program at the University of Colorado in Denver. More recent studies show that the detection of EGFR has no impact on whether a patient will respond to these drugs.

So far, the most reliable way to predict whether a patient will respond to EGFR inhibitors is to test for certain “activating” mutations in the gene that encodes KRAS—a protein that transmits growth signals from EGFR—which occur in 30 to 50 percent of colorectal cancers. New studies show that patients whose tumors express a mutated version of KRAS will not respond to Erbitux or Vectibix.

“The trouble with the KRAS mutation is that it’s downstream of EGFR,” explains Goldberg, “It doesn’t matter if you plug the socket if there’s a short downstream of the plug. The mutation turns [EGFR] into a switch that’s always on.” But this doesn’t mean that having normal, or wild-type, KRAS is a fail-safe.

“It isn’t foolproof,” cautions Goldberg. “If you have wild-type KRAS, you’re more likely to respond, but it’s not a guarantee.” Tumors shrink in response to these drugs in up to 40 percent of patients with wild-type KRAS, and progression-free and overall survival is increased.

While it has been proven that KRAS status can predict whether a patient will respond to an EGFR inhibitor, it is not clear whether it affects overall prognosis—in other words, the overall survival of a patient regardless of treatment strategy. Some prospective studies have suggested that mutated KRAS is associated with shorter overall survival but others revealed no difference. And KRAS status did not influence overall survival in patients who received supportive care alone.

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