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Journal of Clinical Oncology, Vol 22, No 15 (August 1), 2004: pp. 3202 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.100
In Reply:
Instituto Nazionale Tumori, Milan, Italy The letter of Dr Altundag et al raises a few important questions for the interpretation of circulating DNA levels. With respect to human telomerase reverse transcriptase (hTERT) specificity, it was not our intention to use hTERT genomic amplification as a tumor-associated marker, but instead, we simply used it as a marker to quantify, by real-time polymerase chain reaction, the total amount of circulating DNA that includes not only tumor, but also normal DNA, possibly released in the circulation as a result of the tumor-host interaction. To our knowledge to date, the release of DNA into the bloodstream, measured by hTERT copy number, cannot be seen as a tumor-specific marker for lung cancer or any other tumor site. Nonetheless, we could measure with unprecedented accuracy the amount of plasma DNA in a large series of lung cancer patients and matched controls, and demonstrate a highly significant difference between these two groups. On the other hand, a certain degree of cell-type specificity could be hypothesized since in our analysis (unpublished data), median hTERT DNA plasma levels in 60 patients with lung metastases from other cancers (15 ng/mL) or in 11 patients with inflammatory diseases (12 ng/mL) were lower than those detected in patients with non–small-cell lung cancer (NSCLC; 24 ng/mL). We stated in the article that no association was observed between pathologic stage and plasma DNA at multivariate analysis. More specifically, median DNA levels were 25 ng/mL for stage 1A, 21 ng/mL for stage 1B, 35 ng/mL for stage 2, and 23 ng/mL for stage 3 (Kruskall-Wallis test P = .30). This observation is consistent with our prior reports of a high frequency of microsatellite alterations, p16INK4A hypermethylation, and p53 mutations in plasma DNA of early-stage NSCLC.1-3 Having tested the entire cohort of 1,035 high-risk individuals enrolled onto our pilot trial, we will assess in the near future if very small computed tomography (CT) –detected lung cancers (< 1 cm) show a level of DNA release into plasma similar to the one observed in symptomatic patients with NSCLC, thus demonstrating the real contribution of this polymerase chain reaction assay to early lung cancer detection. It is certainly correct to underline that some overlapping occurred in the distribution of plasma DNA between cases and controls, which is also evident in the confidence limits of Table 2 of the article.4 Choosing a low DNA cutoff to designate a person as "positive" would increase diagnostic sensitivity at the expense of false-positives and poorer specificity. On the contrary, selecting a high DNA cutoff would then maximize the specificity at the expense of sensitivity, increasing the number of false-negatives. As a matter of fact, it is unlikely that a single tumor marker could perfectly discriminate lung cancer patients from individuals without disease. The ultimate value of plasma DNA quantification may not be to replace spiral CT as a primary tool for early lung cancer detection, but instead to improve the interpretation of suspicious CT or positron-emission tomography images or to decide how often to repeat spiral CT based on individually tailored risk. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Sozzi G, Musso K, Ratcliffe C, et al: Detection of microsatellite alterations in plasma DNA of non-small cell lung cancer patients: A prospect for early diagnosis. Clin Cancer Res 5:2689-2692, 1999
2. Bearzatto A, Conte D, Frattini M, et al: P16(INK4A) hypermethylation detected by fluorescent methylation-specific PCR in plasmas from non-small cell lung cancer. Clin Cancer Res 8:3782-3787, 2002 3. Andriani F, Conte D, Mastrangelo T, et al: Detecting lung cancer in plasma with the use of multiple genetic markers. Int J Cancer 108:91-96, 2004[CrossRef][Medline]
4. Sozzi G, Conte D, Leon M, et al: Quantification of free circulating DNA as a diagnostic marker in lung cancer. J Clin Oncol 21:3902-3908, 2003 Related Article
Related Correspondence
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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