|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2008.19.5024 on November 10 2008 © 2008 American Society of Clinical Oncology.
Using Predictive Biomarkers to Select Patients With Advanced Colorectal Cancer for Treatment With Epidermal Growth Factor Receptor Antibodies
Department of Medicine, Royal Marsden Hospital, Sutton, United Kingdom As a result of the data emerging during the course of 2008, including presentations at the 44th Annual Meeting of the American Society of Oncology, it has generally been accepted that selection of patients with metastatic colorectal cancer (mCRC) for treatment with epidermal growth factor receptor (EGFR) antibodies—cetuximab or panitumumab—is reliant on the KRAS status of the tumor. For some time, KRAS had been suggested as a predictive marker for resistance to EGFR monoclonal antibodies, but Amado et al1 were the first to publish conclusive data demonstrating the relationship between KRAS status and panitumumab efficacy in their analysis of tumor sections from participants in a randomized phase III trial comparing panitumumab with best supportive care. They found that both response to panitumumab monotherapy and improvement in progression-free survival (PFS) were confined to patients with wild-type (WT) KRAS. KRAS mutations were detected in 43% of patients, none of whom responded to panitumumab. Analyses of KRAS status and response to cetuximab have revealed similar results. For instance, in the first-line treatment of mCRC, a retrospective analysis of the impact of KRAS status on PFS and response rate on patients treated with folinic acid, fluorouracil, and irinotecan with or without cetuximab for mCRC within the Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer trial identified KRAS mutations in 35.6% of KRAS-assessable patients.2 For KRAS WT patients, both PFS (9.9 v 8.7 months; HR, 0.68; P = .017) and response rate (59.3% v 43.2%; P = .0025) were significantly improved by the addition of cetuximab to folinic acid, fluorouracil, and irinotecan. In contrast, for patients with KRAS mutations, there was no significant difference in either PFS (7.6 v 8.1 months; HR, 1.07; P = .47) or response rate (40.2% v 36.2%; P = .46) with the addition of cetuximab. For patients treated with first-line infused fluorouracil, folinic acid, and oxaliplatin with or without cetuximab in the Oxaliplatin and Cetuximab for First-Line Treatment of Metastatic Colorectal Cancer study, the improved response rate and PFS associated with cetiximab was also limited to those with KRAS WT tumors.3 In fact, in this study, patients with mutated KRAS receiving cetuximab had poorer outcomes compared with those receiving infusional fluorouracil, leucovorin, and oxaliplatin alone. Based on these results, it is now recommended that KRAS testing to exclude the presence of mutations should be performed when considering either panitumumab or cetuximab in the treatment of advanced colorectal cancer. Ligand-receptor activation of the EGFR at the cell surface results in homo- or heterodimerization of the receptors and triggers activation of downstream signaling pathways.4 The incidence of KRAS mutations in colorectal tumors is approximately 35% to 45%. KRAS mutations can result in constitutive activation of the Ras-Raf-MAP-kinase pathway, one of the major EGFR downstream pathways, and therefore confer resistance to EGFR antibodies.5 Nonmutated KRAS does not, however, guarantee benefit from treatment with EGFR monoclonal antibodies. Consequently, even with routine testing of KRAS status, a significant proportion of patients will be exposed to these drugs and their associated toxicity without deriving any benefit. In this issue of Journal of Clinical Oncology, Di Nicolantonio et al6 evaluate the role of BRAF mutations as prognostic or predictive factors for response to cetuximab or panitumumab and explore potential ways to circumvent inherent pathways of resistance. In this hypothesis-generating study, a retrospective analysis of 113 patients treated with either cetuximab or panitumumab was conducted. Additionally, a cellular analysis of the effect of the BRAF V600E allele on response to cetuximab or panitumumab was performed. The presence of KRAS mutations in this population was 30%. As expected, KRAS mutations were associated with a lack of response to EGFR antibodies (P = .011) and shorter PFS (P = .0275) compared with KRAS WT tumors. Twenty-eight percent of KRAS WT patients responded to either cetuximab (alone or in combination with irinotecan) or panitumumab. BRAF mutations (BRAF V600E allele) were identified in 11 patients (10% of the population evaluated; 14% of KRAS WT patients). BRAF and KRAS mutations were mutually exclusive, as observed in previous studies.7 Supporting the authors’ hypothesis that in KRAS WT tumors, BRAF mutations could have predictive value, none of the 11 BRAF-mutated tumors responded to treatment. Similarly, in the laboratory, colorectal cancer cell lines carrying the BRAF V600E allele were highly refractory to cetuximab and panitumumab. Conversely, all 22 patients who responded to KRAS WT also had BRAF WT. BRAF-mutated tumors were also associated with shorter PFS and overall survival irrespective of KRAS status (P = .0107 and P < .0001, respectively), suggesting a potential role of BRAF as a prognostic biomarker. Interestingly, targeting BRAF-mutated cell lines with the combination of cetuximab and sorafenib resulted in much higher response rates than those observed with exposure to either agent alone—an effect that could be exploited clinically if validated. In summary, these are interesting results that may provide some insight into the mechanisms underlying inherent resistance to EGFR monoclonal antibodies and possible therapeutic approaches to induce sensitivity. The results are somewhat limited by the retrospective nature of the study, the relatively small numbers, and the treatment of patients outside the context of a randomized clinical trial. In particular, the lack of a non-EGFR antibody treatment control arm makes it difficult to form a conclusive statement on the prognostic impact of BRAF mutations. However, the reported response rates are consistent with currently available literature.8-10 Clearly, KRAS or BRAF mutations are not the only factors influencing response to EGFR monoclonal antibodies. In this study, two patients (6%) with KRAS mutations responded to treatment; however, it is possible that these patients may have received a combination of irinotecan and cetuximab and may not have been truly irinotecan refractory. On the other hand, 41% of patients had neither KRAS nor BRAF mutations and yet still did not respond to EGFR antibody-containing therapy. Ongoing identification and evaluation of other predictive biomarkers are imperative to improve the selection of candidates for treatment. The Bowel Oncology with Cetuximab Antibody (BOND) study,8 comparing irinotecan plus cetuximab with cetuximab alone in irinotecan-refractory patients, was pivotal in establishing the role of cetuximab as a valid therapy, with response rates of 22.9% in the combination-therapy group and 10.8% in the monotherapy group. Entry criteria to BOND mandated EGFR expression by immunohistochemistry (IHC) in either the primary tumor or at least one metastatic lesion. From the results of BOND, it became apparent that the degree of EGFR expression (either by percentage of staining cells or staining intensity) did not correlate with response. Subsequent studies have demonstrated a response to cetuximab in some patients who do not express the EGFR by IHC.11,12 A possible explanation for this observation is that given its inherent subjectiveness, IHC is a suboptimal method for assessing EGFR status. It is, however, plausible that the percentage of active EGFRs is more important when predicting EGFR antibody sensitivity. Phosphorylated EGFR is a surrogate marker of EGFR activity and has been associated with response to gefitinib in both pulmonary adenocarcinoma and colorectal cancer cell lines.13,14 Further evaluation of the role of phosphorylated EGFR as a predictive marker for response to cetuximab and panitumumab is warranted. Another potential biomarker for response to EGFR antibodies is the EGFR-associated rash. The severity of the characteristic maculopapular rash associated with EGFR blockade has been correlated with response to cetuximab and improved survival in BOND and other studies.8 Tejpar et al15 have assessed the impact of KRAS status on efficacy within the Evaluation of Various Erbitux Regimens by Means of Skin Tumor Biopsies trial, which was designed to investigate the role of cetuximab-dose escalation according to severity of skin rash. Patients randomly assigned to the dose-escalation arm achieved higher response rates and PFS compared with those acting as controls. Subsequent analysis of KRAS status indicates that dose escalation does not improve response to cetuximab in patients with KRAS mutations; however, for patients with KRAS WT, severity of skin toxicity correlates with a greater PFS, suggesting that skin toxicity and KRAS status are independent predictors of efficacy.16 Dose escalation to induce response in nonresponding patients with KRAS WT may therefore be a valid therapeutic maneuver. It is possible that dose escalation maximizes blockade of upregulated active EGFRs. Alternatively, soluble EGFRs, which have been identified in breast and ovarian cancers, may form complexes with EGFR antibodies, thereby reducing available circulating EGFR antibody levels. Hence, increasing cetuximab or panitumumab dose may overcome this phenomenon.17,18 Increased EGFR gene copy number (GCN) has also been proposed as a potential marker of EGFR activity, with improved response observed in at least two studies.19,20 These results, however, were not reproduced in other studies, indicating that further clarification of the role of EGFR GCN in mCRC is required.12,21 The differing methods of assessing EGFR GCN (fluorescent or chromosomal in situ hybridization and quantitative polymerase chain reaction) may partially explain the discrepant results, and highlight the need for standardized and easily reproducible methods of assessing biomarkers. High mRNA levels of the EGFR ligands epiregulin and amphiregulin have been associated with increased responsiveness to cetuximab, and it is thought that tumors with these characteristics may be particularly dependent on the EGFR for growth.21 Improved outcome has been reported in patients with KRAS WT with high epiregulin and amphiregulin expression who were treated with cetuximab.22 Additional data suggest that other EGFR downstream pathways such as the PI3K/PTEN/AKT/mTOR and JAK/STAT pathways are also important when considering mechanisms of EGFR antibody resistance (Fig 1). PTEN mutations occur in approximately 20% of sporadic CRC.23 At least three studies have correlated either loss of PTEN gene function/expression (characterized by IHC or polymerase chain reaction [PCR]) or mutations in PI3KCA with nonresponsiveness to cetuximab.24-26 These findings are consistent with PTEN`s known role as a tumor suppressor via negative regulation of PI3K, and validate results previously observed in cell line studies.27
Although prospective validation of these and other biomarkers within the context of randomized clinical trials is required before adoption into routine clinical practice, these studies emphasize the importance of understanding the mechanisms of oncogenesis at a molecular level. It seems likely that additional testing of patients with KRAS WT for BRAF mutations will further enrich the population that should be considered for treatment with EGFR antibodies. As demonstrated by the study by Di Nicolantonio et al6 and the Evaluation of Various Erbitux Regimens by Means of Skin Tumor Biopsies trial, identifying the possible mechanisms of resistance to EGFR antibodies may also allow development of therapeutic strategies to overcome resistance in different subsets of patients. Ideally, biomarkers should provide a definitive answer to the question of whether a response to EGFR inhibitors is expected, and should not be prone to subjective interpretation. A further consideration is whether biomarkers represent events occurring early or late in the carcinogenesis pathway, with the latter potentially requiring rebiopsy of metastatic lesions if there is discordance with the primary tumor. With ongoing collaborative efforts between clinicians, scientists, and pathologists, tailoring treatment to individual patients is slowly but surely becoming a reality. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: David Cunningham, Amgen Inc (C) Stock Ownership: None Honoraria: None Research Funding: David Cunningham, Amgen Inc, Merck Serono Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Manuscript writing: Rachel Wong, David Cunningham Final approval of manuscript: Rachel Wong, David Cunningham
ACKNOWLEDGMENTS The authors acknowledge NHS funding to the NIHR Biomedical Research Centre. NOTES published online ahead of print at www.jco.org on November 10, 2008 REFERENCES
1. Amado RG, Wolf M, Peeters M, et al: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626-1634, 2008 2. Van Cutsem E, Lang I, D'haens G, et al: KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. J Clin Oncol 26:5s, 2008 (suppl; abstr 2)[CrossRef] 3. Bokemeyer C, Bondarenko I, Hartmann J, et al: KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience. J Clin Oncol 26:178s, 2008 (suppl; abstr 4000) 4. Mendelsohn J, Baselga J: Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21:2787-2799, 2003 5. Milano G, Etienne-Grimaldi MC, Dahan L, et al: Epidermal growth factor receptor (EGFR) status and K-Ras mutations in colorectal cancer. Ann Oncol 2008 10.1093/annonc/mdn416 [epub ahead of print on July 15, 2008] 6. Di Nicolantonio F, Martini M, Molinari F, et al: BRAF wild-type is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol doi:10.1200/JCO.2008.18.0786 [epub ahead of print on November 10, 2008] 7. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al: Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 67:2643-2648, 2007 8. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004 9. Jonker DJ, O'Callaghan CJ, Karapetis CS, et al: Cetuximab for the treatment of colorectal cancer. N Engl J Med 357:2040-2048, 2007 10. Van Cutsem E, Peeters M, Siena S, et al: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658-1664, 2007 11. Chung KY, Shia J, Kemeny NE, et al: Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 23:1803-1810, 2005 12. Lenz HJ, Van Cutsem E, Khambata-Ford S, et al: Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 24:4914-4921, 2006 13. Hijiya N, Miyawaki M, Kawahara K, et al: Phosphorylation status of epidermal growth factor receptor is closely associated with responsiveness to gefitinib in pulmonary adenocarcinoma. Hum Pathol 39:316-323, 2008[CrossRef][Medline] 14. Van Schaeybroeck S, Karaiskou-McCaul A, Kelly D, et al: Epidermal growth factor receptor activity determines response of colorectal cancer cells to gefitinib alone and in combination with chemotherapy. Clin Cancer Res 11:7480-7489, 2005 15. Tejpar S, Peeters M, Humblet Y, et al: Phase I/II study of cetuximab doseescalation in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST): Pharmacokinetic (PK), pharmacodynamic (PD), and efficacy data. J Clin Oncol 25:18s, 2007 (suppl; abstr 4037) 16. Tejpar S, Peeters M, Humblet Y, et al: Relationship of efficacy with KRAS status (wild type versus mutant) in patients with irinotecan-refractory metastatic colorectal cancer (mCRC), treated with irinotecan (q2w) and escalating doses of cetuximab (q1w): The EVEREST experience (preliminary data). J Clin Oncol 26:178s, 2008 (suppl; abstr 4001) 17. Baron AT, Cora EM, Lafky JM, et al: Soluble epidermal growth factor receptor (sEGFR/sErbB1) as a potential risk, screening, and diagnostic serum biomarker of epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev 12:103-113, 2003 18. Lafky JM, Baron AT, Cora EM, et al: Serum soluble epidermal growth factor receptor concentrations decrease in postmenopausal metastatic breast cancer patients treated with letrozole. Cancer Res 65:3059-3062, 2005 19. Moroni M, Veronese S, Benvenuti S, et al: Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: A cohort study. Lancet Oncol 6:279-286, 2005[CrossRef][Medline] 20. Sartore-Bianchi A, Moroni M, Veronese S, et al: Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab. J Clin Oncol 25:3238-3245, 2007 21. Khambata-Ford S, Garrett CR, Meropol NJ, et al: Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25:3230-3237, 2007 22. Tejpar S, De Roock W, Biesmans B, et al: High amphiregulin and epiregulin expression in KRAS wild type colorectal primaries predicts response and survival benefit after treatment with cetuximab and irinotecan for metastatic disease. ASCO Gastrointestinal Cancers Symposium (abstr 411), Orlando, FL, January 25-27, 2008 23. Nassif NT, Lobo GP, Wu X, et al: PTEN mutations are common in sporadic microsatellite stable colorectal cancer. Oncogene 23:617-628, 2004[CrossRef][Medline] 24. Perrone F, Lampis A, Orsenigo M, et al: PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol 2008 10.1093/annonc/mdn541 [epub ahead of print on July 31, 2008] 25. Frattini M, Saletti P, Romagnani E, et al: PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer 97:1139-1145, 2007[CrossRef][Medline] 26. Loupakis F, Pollina L, Stasi I, et al: Evaluation of PTEN expression in colorectal cancer (CRC) metastases (mets) and in primary tumors as predictors of activity of cetuximab plus irinotecan treatment. J Clin Oncol 26:178s, 2008 (suppl; abstr 4003) 27. Jhawer M, Goel S, Wilson AJ, et al: PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res 68:1953-1961, 2008
Related Article
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
