Role of Biologics in Colon Cancer: Still Not Clear.

Patients with metastatic colorectal cancer are living more than a year longer today than they did one decade ago. Because progress has been made in almost every aspect of cancer care over that time period, it is difficult to isolate the factors most responsible for these improvements. However, drugdevelopment for colorectal cancer has certainly contributed. Irinotecan and oxaliplatin became available in approximately 2000 and jumpstarted the notion that metastatic colorectal cancer was a treatable disease. The approval of the first threebiologicswithactivity inmetastatic colorectal cancer—bevacizumab, cetuximab, and panitumumab—followed and led to a series of combination studies of chemotherapy and biologics that have defined the current standards. In this issue of Journal of Oncology Practice, Mahipal and Grothey offer the chronology, data, and case-based recommendations regarding how to deploy these agents in first-line treatment of metastatic colorectal cancer. It is important to put this subject into context. The biologics in first-line treatment are added to chemotherapy, which is the mainstay in the management of metastatic colorectal cancer.The termbiologics was coined to represent substances that were expected to affect biologic pathways without off-target toxicities, and in an ideal world, their use would be informed by companion biomarkers. However, there are no positive predictive biomarkers (yet) for thesebiologics inmetastaticcolorectalcancer. This may explain why patients with metastatic colorectal cancer have derived less benefit than was expected from biologic agents. When cetuximab was approved by the US Food and Drug Administration, for example, tumor expression of the epidermal growth factor receptor (EGFR) was thought necessary.We soon learned that the presence of the receptor (at least as receptor density could be measured) is not necessary for patients to accrue benefit from agents that target EGFR (cetuximab or panitumumab). These observations were the preamble to a retrospective series suggesting that mutations in the KRAS gene at exon 2 confer resistance to EGFR antibodies. Subsequent research suggested that mutations in KRAS exon 3 and exon 4 hotspots as well as parallel mutations inNRAS are also associated with a lack of benefit from EGFR antibodies. These recent additionsshrinkthenumberofpatientspreviously eligible toreceivecetuximaborpanitumumab by approximately 20%, and because these mutations are also prognostic, survival results have become inflated for the all-RAS wildtype cohort (while the excluded patients experience relatively poorer results). Moreover, higher sensitivity assays are detecting KRAS-mutant clones in tumors previously classified as KRAS wild type, which, depending on the RAS mutation detection threshold used to exclude use of EGFR antibodies,may also seem to improve survival. The incorporation of these mutational analyses seems to apply equally to cetuximab and panitumumab, which may be interchangeable even though they are different molecules. However, patients who have spent time in the mid-southern United States have a 20% or greater risk of cetuximab-induced hypersensitivity