|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 26, No 8 (March 10), 2008: pp. 1389-1390 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.2439
In Reply:Department of Medical Oncology, AO Ospedali Riuniti-Università Politecnica delle Marche, Ancona, Italy
Department of Pathology, AO Ospedali Riuniti-Università Politecnica delle Marche, Ancona, Italy We thank Dr Brandi et al for their comments about our article.1 We agree that the question of reliable identification and distinction between predictive and prognostic factors in colorectal cancer should be considered of crucial relevance to the management of the patients diagnosed with this disease, particularly after the introduction of anti-epidermal growth factor receptor (EGFR)–targeted treatment options. Unfortunately, distinguishing between the predictive and prognostic roles of a given factor (either clinical or biologic) is frequently challenging as the characteristics may overlap in the patient population. A fitting example in colorectal cancer patients treated with cetuximab is skin rash. Clinical studies have demonstrated that skin rash may help clinicians identify responding patients, thus suggesting a predictive role for this clinical characteristic.2 However, cetuximab-induced skin rash is also associated with an improvement in survival parameters, complicating its classification into an exclusive category (ie, predictive or prognostic). It is also important to note that nuclear factor kB (NF-kB) expression has been correlated to chemotherapy resistance in solid tumors already.3,4 However in our analysis, all patients included were deemed irinotecanrefractory, and therefore it is unlikely that NF-kB expression would have a role in predicting clinical outcome after chemotherapy alone in this group, whereas an interaction with the cetuximab-induced EGFR blockade seems more probable. We are aware that activated (ie, phosphorylated) EGFR expression would probably have been of greater value if the molecular link between EGFR and NF-kB was analyzed. The observation by Dr Brandi et al highlights an interesting area for additional analysis. Nevertheless, the aim of our study was to investigate the predictive role of NF-kB expression in colorectal cancer patients receiving cetuximab-irinotecan, and all consideration about the apparent lack of correlation between total EGFR immunohistochemical expression and NF-kB observed in some patients should be considered purely speculative. The suggestion that activation of NF-kB in human colorectal mucosa may be related to a chronic inflammatory status sustained by intestinal microflora is intriguing. NF-kB–altered expression may, in fact, occur in response to a variety of stimuli (eg, cytokines, viruses, and DNA-damaging agents), but it has been reported to be constitutively activated in tumors as a late event in the neoplastic process.5,6 No data are available from our study about NF-kB status in normal colonic mucosa adjacent to tumor, and therefore no definitive conclusions can be drawn. The correlation between NF-kB status in primary colon cancer and corresponding metastases was discernable in only 11 patients in our series, and indicated a consensual expression of NF-kB in all cases. These findings seem to confirm that NF-kB–altered expression may occur late in colon cancer carcinogenesis. However, the small sample size available for this analysis may represent an unpredictable confounding factor. EGFR downstream signaling pathway, its interaction with molecular mechanism related to neoplastic cell apoptosis (such as NF-kB), and other biologic determinants (ie, k-ras), are becoming increasingly relevant due to their role in determining resistance to anti-EGFR–targeted antibodies. Therefore, it is encouraging that researchers worldwide are now trying to clarify a biologic picture vital to our patients’ treatment. 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 tumor expression predicts response and survival in irinotecan-refractory metastatic colorectal cancer treated with cetuximab-irinotecan therapy. J Clin Oncol 25:3930-3935, 2007 2. 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 3. Abdel-Latif MM, O’Riordan J, Windle HJ, et al: NF-kB activation in esophageal adenocarcinoma relationship to Barret’s metaplasia, survival and response to neoadjuvant chemoradiotherapy. Ann Surg 239:491-500, 2004[CrossRef][Medline] 4. Izzo JG, Malhotra U, Wu T-T, et al: Association of activated transcription factor nuclear factor kB with chemoradiation resistance and poor outcome in esophageal carcinoma. J Clin Oncol 24:748-754, 2006 5. 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] 6. Bours V, Bentires-Alj M, Hellin AC, et al: Nuclear factor-kB, cancer and apoptosis. Biochem Pharmacol 60:1085-1090, 2000[CrossRef][Medline] Related Correspondence
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
