Biomarkers Predicting Clinical Outcome of Epidermal Growth Factor Receptor–Targeted Therapy in Metastatic Colorectal Cancer

Salvatore Siena; Andrea Sartore-Bianchi; Federica Di Nicolantonio; Julia Balfour; Alberto Bardelli

Disclosures

J Natl Cancer Inst. 2009;101(19):1308-24. 

In This Article

Discussion and Future Perspectives

Although the link between clinical benefit and overexpression of the molecular target is clear for trastuzumab and imatinib and their respective targets (HER2 and the BCR-ABL tyrosine kinase), experience has shown that positive expression of EGFR as shown by immunostaining is not predictive of response to EGFR inhibitors. It is now clear that tumor growth can be driven by constitutive activation of signaling pathways downstream of the EGFR, such as the RAS–MAPK–PI3K pathway. Oncogenic activation of components in these pathways can bypass the EGFR-driven signaling cascade and impair the clinical efficacy of anti-EGFR monoclonal antibodies. Such activation can occur via mutations in oncogenes such as KRAS or BRAF on one side of the EGFR-mediated pathway or by PIK3CA mutation or loss of tumor suppressor genes such as PTEN on the opposite side of the cascade[72] (Figure 1). These findings may provide some explanation for the rather modest objective response rates that have been achieved with clinical trials of EGFR inhibitors to date, as well as the disparities observed between clinical and preclinical findings. It should also be noted that preclinical models are based on particular tumor subtypes that may not be representative of most tumors encountered in clinical practice.

Table 4 summarizes potential biomarkers that may be related to primary response to the anti-EGFR monoclonal antibodies, panitumumab and cetuximab. Overall, presently available data reviewed in this article provide convincing evidence that activating mutations of KRAS, which are present in a substantial proportion of patients with metastatic colorectal cancer, predict lack of response to anti-EGFR monoclonal antibody treatment.[27–29,33,34,55,60] This finding is consistent with observations from use of EGFR tyrosine kinase inhibitors in the treatment of non–small cell lung cancer, although KRAS mutations are less common in lung tumors.[66,67]

KRAS testing is now being integrated into clinical practice. The European Medicines Agency's conditional approval of panitumumab monotherapy in the setting of chemorefractory metastatic colorectal cancer specified wild-type KRAS as a selection marker.[134] Current data indicate that objective response rates of up to 22% can be expected in such patients ( Table 2 ). It should be noted that clinical benefit is not confined to objective responders because delaying disease progression can improve clinical symptoms and the patient's quality of life.[135] Wild-type KRAS was more recently identified as a selection marker for cetuximab monotherapy or combination therapy.[136] The European Medicines Agency,[20,130] the US Food and Drug Administration,[137] and the American Society of Oncology[131] now recommend determining tumor KRAS status before initiating treatment with an anti-EGFR monoclonal antibody and restricting such treatment to patients with tumors bearing wild-type KRAS.

Because of the complexity of the EGFR signaling system, it is likely that predictive algorithms will be developed for metastatic colorectal cancer that incorporate several molecular biomarkers. For instance, combining analysis of KRAS status with determination of BRAF and PIK3CA status and PTEN expression may identify additional patients with metastatic colorectal cancer who are unlikely to respond to treatment with an EGFR-targeted monoclonal antibody.[133] However, these additional markers ( Table 4 ) require further validation before they can be incorporated into clinical practice.

Tumors with an increased EGFR gene copy number as assessed by FISH or chromogenic in situ hybridization may be dependent on the EGFR pathway for their survival and growth. There is evidence that normal diploid EGFR gene copy number may predict tumor resistance to EGFR-targeted treatment ( Table 3 ). Again, further research is required to validate this biomarker in larger patient series.[97]

There are clearly a number of technical issues to be overcome, particularly standardization of analytical methods and scoring systems. Lack of standardization may well explain some of the discordant results that have been reported. Certainly, some biomarkers may not prove suitable for translation into clinical practice. However, DNA sequencing of formalin-fixed paraffin-embedded tumor samples is a relatively straightforward method for identifying KRAS mutations. Because KRAS mutation is an early event in colorectal cancer tumorigenesis,[42,43] archived primary tumor tissue can be used to identify patients who are unlikely to respond to EGFR-targeted monoclonal antibodies, even after multiple lines of treatment. A KRAS testing kit from DxS Ltd can identify the following seven somatic mutations in KRAS codons 12 and 13: Gly12Ala, Gly12Arg, Gly12Asp, Gly12Ser, Gly12Cys, Gly12 Val, and Gly13Asp. The polymerase chain reaction–based technique used is highly sensitive but does not detect less frequent changes that can be detected with direct sequencing (eg, Gly13Val, Gly13Ala, and Gly13Cys). Although direct sequencing has the capability to detect all changes at the nucleotide level, it is less sensitive and may occasionally miss mutations, especially if the fraction of tumor vs normal cells is low.[57] Testing will be facilitated by gene panel microarray technology and gene panels that incorporate KRAS testing are being evaluated.[138]

Further work is also required to explore potential early markers of response (in patients already receiving EGFR-targeted treatment) that can be incorporated into the design of future prospective clinical trials and guide therapeutic decisions regarding continuation of treatment in individual patients. Skin toxicity develops at an early stage in treatment with EGFR inhibitors and has been studied extensively as a potential early marker of response, although further work is required.

Virtually all responding tumors eventually "escape" from EGFR-targeted treatment (ie, develop acquired resistance). In the lung cancer setting, acquired resistance to erlotinib or gefitinib has been attributed to development of a secondary mutation within the EGFR catalytic domain.[139] Other potential escape mechanisms include activation of alternative signaling pathways contributing to proliferation and survival, such as those involving activation of HER2, HER3, mesenchymal–epithelial transition factor (C-MET), insulin-like growth factor-I receptor, MAPK, and Akt.[140] Consequently, identification of the molecular basis of acquired resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer should be a priority for future research.

In conclusion, the quest for predictive biomarkers of response to EGFR inhibitor therapy has resulted in a rapidly accumulating body of knowledge that has paved the way for more targeted use of these agents. More rational use of EGFR-targeted agents should provide benefits for patients and health-care providers alike by sparing patients unnecessary treatment and allowing better use of health-care resources. Prospective biomarker-driven studies are now under way, but in the meantime, the identification of wild-type KRAS as a selection biomarker for panitumumab or cetuximab therapy represents an important step toward fulfilling the promise of individualized treatment for metastatic colorectal cancer.

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