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Individualized colon cancer Rx advances beyond KRAS

Individualized colon cancer Rx advances beyond KRAS

ABSTRACT: Predictive and prognostic polymorphisms, such as transporter genes and BRAF mutations, make headway as personalized treatment options for colorectal cancer patients.

SAN FRANCISCO—Routine KRAS testing in colon cancer patients received a major boost in January when ASCO issued a provisional clinical statement in favor of pretreatment genetic screening in metastatic disease. But KRAS is only the first step toward personalized medicine in colorectal cancer, according to reports presented at the 2009 Gastrointestinal Cancers Symposium. In fact, colon cancer treatment is headed in the same direction as breast cancer, with other genetic polymorphisms emerging as both predictive and prognostic. At the symposium, Alan P. Venook, MD, offered an overview on how genetic markers will truly guide treatment planning. In addition, several researchers presented their latest work in the field.

18q deletions
In breast cancer, recurrence scores and pretreatment tests are calculated from tissue samples, said Dr. Venook, professor of clinical medicine at the University of California, San Francisco.

“Can we do the same in colorectal cancer? Would this help determine which stage II patients need chemotherapy?” Dr. Venook asked. “Not only would this optimize patient care but it would help us afford care in an era of escalating costs.”

Fifteen years ago, researchers established that stage II patients with 18q deletions “behaved more like stage III patients” while those with intact 18q almost never succumbed to their disease. Now this information is being used in a clinical trial: ECOG 5202 is stratifying patients (n = 3,125) according to presence or absence of 18q and microsatellite instability, and randomizing them to FOLFOX with or without bevacizumab (Avastin) or to observation.

“I emphasize that this is 15 years from the initial observation that deletion of 18q could be an important marker,” Dr. Venook noted. The 18q deletion will be but one factor in a predictive or prognostic genetic signature. “But we are not far from where our breast cancer colleagues are,” he said.

Downstream events
The importance of the KRAS oncogene, which is downstream of EGFR and is mutated in some 30% or more of colorectal tumors, has been confirmed as being predictive of response to EGFR antibodies (wild-type KRAS) or lack of response (mutated KRAS). Based on a strong body of data, the CALGB/SWOG 80405 trial that Dr. Venook is leading was amended to exclude patients with mutated KRAS, and future trials will follow this lead.

While KRAS is predictive, it does not appear to be prognostic; that is, it is not associated with outcomes independent of treatment. On the other hand, BRAF, the serine-threonine kinase that is the principal effector of KRAS, may be prognostic (see below, abstract 293).

Italian investigators recently reported that V600E mutations in BRAF preclude a response to panitumumab (Vectibix) or cetuximab (Erbitux) in patients with normal KRAS. In their study of 113 subjects, BRAF-mutated patients did not respond to treatment and had significantly shorter progression-free survival (PFS) and overall survival (OS) than patients with wild-type tumors. In other words, to obtain benefit from EGFR antibodies, both wild-type KRAS and wild-type BRAF may be necessary.


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