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Journal of Clinical Oncology, Vol 26, No 8 (March 10), 2008: pp. 1388-1389 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.1845
Activated NF-kB in Colorectal Cancer: Predictive or Prognostic Factor?Institute of Hematology and Medical Oncology "L.A.Seragnoli," Policlinico Sant’Orsola-Malpighi, University of Bologna, Bologna, Italy
Centre of Applied Biomedical Research (CRBA), Policlinico Sant’Orsola-Malpighi, University of Bologna, Bologna, Italy To the Editor: In September 2007, Scartozzi et al1 addressed an important issue related to the identification of a new molecular marker to predict cetuximab efficacy in patients affected by metastatic colorectal cancer. The aim of the work is topical for its clinical implications. The authors studied nuclear factor kB (NF-kB) positivity in primary colorectal tumors defined as having a nuclear immunostaining positivity, which is considered to be activated NF-kB. They found significant differences in partial response, time to progression (TTP), and survival—which are lower for patients with nuclear translocation of NF-kB (NF-kB–positive tumors)—and suggested the role of NF-kB in predicting efficacy of cetuximab (and irinotecan) therapy in advanced colorectal cancer. The authors designed this work based on the biologic link between epidermal growth factor receptor (EGFR) pathway and NF-kB, assuming that the in vivo NF-kB activation may be mediated by EGFR activation. In this article the immunohistochemical analysis of NF-kB translocation was performed only on cancerous intestinal mucosa. We agree with the authors, who state that EGFR-based therapy does not seem to be able to overcome the resistance mediated by NF-kB activation. In fact, if the nuclear translocation of NF-kB is correlated to the EGFR pathway, cetuximab-based therapy should be more efficacious in patients with NF-kB-positive tumors than those with negative tumors (similar to what happens for human epidermal growth factor 2/transtuzumab). On the contrary, the results showed that NF-kB-negative tumors are more sensitive than positive ones. Consequently, the better outcome of patients with negative tumors may not reflect the predictive role of NF-kB on cetuximab (and irinotecan) efficacy, but rather its prognostic value in solid tumors for the correlation with tumor invasion and angiogenesis.2-3 The authors concluded that TTP, survival, and response rate confirm the role of NF-kB in predicting the efficacy of cetuximab; however, the lower TTP and survival can be just the mirror of prognostic value of NF-kB activation. Regarding the response rate, the two populations studied (NF-kB positive and negative) showed an inverse trend of stable disease and partial response. Interestingly, the statistical difference comparing the disease control rate (response + stable disease) of the two groups is not significant. Furthermore, the authors associated the NF-kB activation with EGFR expression studied with immunohistochemistry, considering all known limits related to this method as they themselves considered. In some cases the association between NF-kB activation and EGFR positivity is lost, and the authors explained this aspect with the inadequacy of immunohistochemistry. However, in our opinion this point may be related not only to a methodological issue, but a biologic one as well. In fact, no data in the article are available on activated EGFR (pY1068-EGFR) that should be correlated to nuclear translocation of NF-kB more than total EGFR expression.4 NF-kB–responsive genes positively regulate a major control point in several key cellular processes. The misregulation of the NF-kB pathway by epigenetic mechanisms or mutations is involved in chronic inflammation, immunodeficiency, and cancer (mainly by an increasing antiapoptotic process). Therefore, it is not surprising that the NF-kB can be activated by several factors.5 For instance, constitutive activation of NF-kB in colorectal mucosa, at least in rodents, is due to the presence of intestinal microflora, and it is increased on colonic inflammation in parallel to the increased number of bacteria on inflamed mucosa.6-8 Interestingly, the number of adherent bacteria also in neoplastic mucosa is higher than in adjacent normal mucosa.9 This event may suggest that NF-kB can be activated on cancer mucosa by epigenetic mechanisms, and is probably not a late biologic phenomenon as speculated by the authors. A more accurate interpretation of this aspect can be done by a simultaneous study of the normal adjacent mucosa, or, in a conclusive manner, studying the NF-kB status in metastases. Finally, in order to reach some conclusions on the independent prognostic role of NF-kB with respect to EGFR pathway inhibition from cetuximab, it would be useful to investigate the clinical outcome of NF-kB–positive and–negative cancer patients treated only with chemotherapy or other therapeutic regimens not containing EGFR inhibitors. In conclusion, the authors addressed an important clinical issue and contributed to a better knowledge of biologic background of colorectal cancer as a basis to select patients who are likely to benefit from EGFR inhibitors, but further research on this issue is needed. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Scartozzi M, Bearzi I, Pierantoni C, et al: Nuclear factor-kB expression predicts response and survival in irinotecan-refractory metastatic colorectal cancer treated with cetuximab-irinotecan Therapy. J Clin Oncol 25: 3930-3935, 2007 2. Dolcet X, Llobet D, Pallares J, et al: NF-kB in development and progression of human cancer. Virchows Arch 446:475-482, 2005[CrossRef][Medline] 3. Yu HG, Zhong X, Yang YN, et al: Increased expression of nuclear factor-kappaB/RelA is correlated with tumour angiogenesis in human colorectal cancer. Int J Colorectal Dis 19:18-22, 2004[CrossRef][Medline] 4. Piazzi G, Paterini P, Ceccarelli C, et al: Molecular determination of epidermal growth factor receptor in normal and neoplastic colorectal mucosa. Br J Cancer 95:1525-1528, 2006[CrossRef][Medline] 5. Courtois G, Gilmore TD: Mutations in the NF-kappaB signaling pathway: Implications for human disease. Oncogene 25:6831-6843, 2006[CrossRef][Medline] 6. Clevers H: At crossroads of inflammation and cancer. Cell 118:671-674, 2004[CrossRef][Medline] 7. Greten FR, Eckmann L, Gretn TF, et al: IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118:285-296, 2004[CrossRef][Medline] 8. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, et al: Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118:229-241, 2004[CrossRef][Medline] 9. Martin HM, Campbell BJ, Hart CA, et al: Enhanced Escherichia coli adherence and invasion in Crohn’s disease and colon cancer. Gastroenterology 127:80-93, 2004[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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