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 PMID: 16963729
Umetani N et al
J Clin Oncol 2006 Sep 10;24(26):4270-6
Prediction of breast tumor progression by integrity of free circulating DNA in serum.
2 comments exist on this article.




Not likely to be more clinically useful than current markers

 Rank: 1
BioMed Crit Comm 2009; 2:1719
Posted: Aug 19, 2009    CCID: 1719  
Commentator: Gary Ave. score of this commentator: 2.6 for 30 scored comments.
 
The authors conclude in the Abstract that measuring the length (integrity) of circulating DNA "is a promising molecular biomarker for detecting breast cancer tumor progression and regional lymph node metastases." Neither are likely. 1) Detecting "tumor progression" is a vague concept. One would like to detect the tumor, not merely its progression. A failure to detect the tumor renders the progression issue moot. 2) This assay is unlikely to detect early tumors. The mean serum "integrity" was essentially unchanged among healthy subjects, patients with in-situ, ad patients with stage I tumors (means of 0.13, 0.16, and 0.12, respectively). 3) The DNA integrity was greater in patients with stage II, III, and IV tumors, but these patients are likely to have been already identifiable using existing, non-molecular signs and symptoms. In fact, all patients were identified by such non-molecular techniques before the DNA integrity test was performed. 4) The differences between patients with stage II and higher were also likely to have been reflected using non-molecular tests. Although the mean DNA integrity differed among these three stages, stratification according to conventional measures of disease severity was not performed. It is the omission of the conventional descriptors that makes the test for DNA integrity appear to carry information, for it they had been taken into account, the additional information provided by DNA integrity might have been nil. In Fig. 5, the apparent ability of high DNA integrity values to identify the cases with lymph node metastasis may actually be due to disease severity. DNA integrity perhaps is only a surrogate measure for abnormal physiology, which can be measured in many ways. 5) Figure 4 shows that there was great overlap between the ranges of DNA integrity values for patients negative and positive for lymphovascular invasion. There would be no practical value for characterizing an individual patient. 6) Similarly, the correlation with tumor size (Fig. 3) is statistically significant but weak; the scatterplot shows no discriminating power for use in individual patients.



Imprecise rationale: Proposed mechanism may be invalid

 Rank: 2
BioMed Crit Comm 2009; 2:1720
Posted: Aug 19, 2009    CCID: 1720  
Commentator: Gary Ave. score of this commentator: 2.6 for 30 scored comments.
 
The authors suggest that greater DNA integrity in cancer patient serum might result due to tumor DNA being released from cells having impaired apoptosis, whereas normal cells release DNA upon undergoing apoptosis. This rationale or premise has at least two major flaws. First, when normal cells undergo apoptosis, they are engulfed by phagocytic cells. There is no evidence that circulating free DNA of small size is largely attributable to normal apoptosis. Second, the authors provide no evidence that the large DNA - the DNA with "integrity" - is derived from tumor cells. It is possible that the large DNA derives from small levels of disseminated intravascular coagulation or other physiologic conditions causing fragmentation of blood leukocytes, rather than from tumor DNA. Such an alternate explanation is supported by the finding that circulating large DNA can be found in nonmalignant conditions such as pregnancy (PMID: 14709639) and that leukocyte fragmentation accompanies intravascular coagulation.



Key authors in this publication:

Giuliano AE, Hiramatsu SH, Hoon DS, Martino S, Nakagawa T, Umetani N.


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