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Personalised Cancer TherapyWhat is KRAS and What Does it Mean for PatientsWith Metastatic Colorectal Cancer?Liesbeth Lemmens, BSc, MSc, Coordinator Clinical Trials, Digestive Oncology Department of Gastroenterology,University Hospitals Leuven, BelgiumIntroductionEGFR as a Therapeutic Target in Colorectal CancerRecent advances in understanding the molecular basis of cancer The EGFR pathway plays a critical role in tumour growth andhave revolutionised medical oncology. Scientists have identified progression (7, 8). The EGFR-mediated signalling activates multiplefunctionally important proteins that are involved in regulating the pathways that result in cell proliferation and survival (Figure 1). Thegrowth, survival, and metastatic properties of tumour cells. These abnormal activation of EGFR is implicated in many types of cancers,proteins have served as targets for the rational design and discovery including 75% to 90% of CRC, and seems to reflect a more aggressiveof novel treatments, referred to as “targeted therapies” (1, 2). pathology and clinical behaviour, such as more tumour angiogenesis,Although many of these novel targeted agents have been shown to proliferation, metastasis, and survival (9-11). As a result, EGFR hasimprove outcomes in clinical trials, it is clear that not all patients been identified as a logical target in cancer treatment, and therapiesbenefit from the therapies. The current research challenge, therefore, have been developed to inhibit this signalling pathway.is to identify indicators that can predict response to treatment (3).The activity of EGFR can be inhibited by either small molecule“Biomarker” is defined as “a characteristic that is objectivelyinhibitors or by monoclonal antibodies. Small molecule inhibitors,measured and evaluated as an indicator of normal biologicalsuch as erlotinib (Tarceva ® ), selectively inhibit the enzyme (tyrosineprocesses, pathogenic processes, or pharmacologic responses to kinase) activity of EGFR inside the cell; thus, they are referred to asa therapeutic intervention (4).” Whereas prognostic biomarkers tyrosine kinase inhibitors or TKIs (12). No TKI has been approvedindicate clinical outcomes independent of treatment, predictive for use in CRC to date. Monoclonal antibodies, such as cetuximabbiomarkers determine the response of a tumour to a specific(Erbitux ® ) and panitumumab (Vectibix ® ), target EGFR outside thetherapy. Consequently, predictive biomarkers are used to identify cell by blocking ligand binding and subsequent activation of EGFRthe treatment option that will result in the best patient outcomes. By signalling (8). In randomised clinical trials, both of these anti-EGFRalso identifying patients who are not likely to benefit from therapy, antibodies have been shown to improve patient outcomes andpredictive biomarkers will prevent exposure to and toxicity from provide alternate treatment options for patients with metastatic CRCineffective treatments while preventing treatment delays with other (mCRC) (13-19).potentially effective regimens and reducing healthcare costs.Despite promising results in clinical trials, not all patients respondThis article explains how personalised medicine may become a reality to cetuximab and panitumumab; in clinical trials, monotherapy withfor patients who have colorectal cancer (CRC) by allowing healthcare these agents yielded response rates of approximately 10% andproviders to select appropriate treatments for patients on the basis disease stabilisation rates of approximately 30% (13-15, 20). Theseof their specific genetic profile. Scientists have recently identified a results led to a search for a biomarker that would help identifydifferential response to antibodies that target the epidermal growth patients who were likely to respond to anti-EGFR therapy.factor receptor (EGFR) based on the presence or absence of amutation of a specific gene called Kirsten RAS or KRAS. KRAS is a Biomarkers for Anti-EGFR Therapypart of the rat sarcoma oncogene virus (ras) family, which encodes EGFR overexpression as a biomarkerthe KRAS protein (5, 6). The biology of EGFR and KRAS, the effect of Preclinical data had suggested that sensitivity to anti-EGFR agentsthe KRAS mutation, and the studies that have led to the identification was linked to levels of expression of EGFR, and patients participatingof KRAS as a clinically relevant biomarker will be discussed.in the initial clinical trials were required to have detectable EGFRprotein expression as determined by immunohistochemistry (IHC)Figure 1: Relationship between EGFR pathway and KRAS in colorectal testing. However, objective responses were seen in patientscancerregardless of EGFR expression status, and the use of EGFR IHC asa predictive marker of response has been questioned despite theproduct labels’ requirement for testing (21-23).Several studies are also evaluating whether the presence of a largenumber of copies of the EGFR gene in the tumour cells (comparedto 2 copies in normal cells) are predictive of response; to date thesestudies have yielded conflicting results (22, 24-27). Thus, levels ofEGFR protein or gene in tumour cells are not considered predictivefor response based on currently available measurement methods.28 - newsletter fall 2008
Skin toxicity as a biomarkerEGFR inhibitors are associated with the development of manyadverse effects, such as hypersensitivity reactions, gastrointestinaldisorders, metabolic disorders (hypomagnesaemia and secondaryhypocalcemia), and dermatologic toxicity (28). Several studieshave shown that adverse skin reactions consistently correlatewith response to cetuximab and panitumumab (29). In fact theoccurrence of a more severe rash upon treatment with cetuximab orpanitumumab predicted a longer progression-free survival (PFS), aswell as overall survival (13-15, 30).Skin rash, however, is not considered a reliable biomarker becauseof the lack of toxicity criteria designed to measure the effect of EGFRinhibitors. Other factors, such as the optimal timing for measuringskin toxicity, also need to be determined (31). In addition, someresponders to anti-EGFR treatments do not display a rash, and somepatients with a severe rash do not respond to treatment (9, 13, 15).Therefore, an emerging issue in the appropriate use of EGFR-targetedtherapy in patients with CRC is to identify an effective method forselecting patients who will most likely benefit from these agents.KRAS: The Quest for Biomarkers of ResponseKRAS is an important protein that plays a crucial role in regulatingcell division. KRAS receives signals from several receptors, includingEGFR, and upon activation regulates other proteins located furtherdown in the complex signalling cascade, which in turn eventuallystimulate cell proliferation and survival (Figure 1). Signalling throughthese cascades is normally tightly regulated. A loss of control of theKRAS pathway can lead to hyperactive signalling in tumour cells andresult in tumour angiogenesis, proliferation, metastasis, and survival(5, 6, 32).Mutations of the KRAS gene are among the most common geneticalterations in solid tumours (5). It was estimated that 35% to 45% ofpatients who have CRC have a mutated form of the KRAS gene, withthe remaining patients having a nonmutated or wild-type gene (20,33, 34). These mutations result in a constitutively activated KRASprotein. In other words, the mutation leaves the KRAS protein alwaysturned “on,” in order that signalling within the cancer cell continueseven in the absence of extracellular stimuli (5, 6, 32). As a result,antitumour effects mediated by anti-EGFR antibodies are bypassedby the mutated KRAS protein (Figure 2). In contrast, in tumours withwild-type KRAS, the signalling pathway is turned on only in responseto ligands, such as epidermal growth factor. This allows for effectiveblockade of the KRAS signalling pathway by antibodies that targetEGFR (5, 6, 32).Early evidence from uncontrolled studies has suggested a correlationbetween KRAS gene mutations and a poorer prognosis (35, 36),leading researchers to ask if KRAS is an appropriate biomarker forpatient selection for anti-EGFR therapy in CRC and other EGFRassociatedcancers.First Step Towards Tailored mCRC TherapyRecently, several studies have indicated that KRAS gene mutationstatus determines whether patients are likely to respond to EGFRtargetedtherapies, such as panitumumab and cetuximab, for mCRC.In 2007, the European Medicines Agency (EMEA) ruled that datawere sufficiently convincing to mandate KRAS testing as part ofthe conditional marketing approval for panitumumab in mCRC. Thisdecision was based on a prespecified biomarker subset analysis ofthe phase 3 trial that showed the superiority of panitumumab overFigure 2: Mechanism by which mutant KRAS overcomes inhibition by ant-EGFR antibodiesnewsletter fall 2008 -29
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