DISCUSSION
Patients with CAD have high probabilities of developing tumors, given that the incidence of cancer increases with age1, tobacco consumption and some dietary patterns that also promote CAD2, 3. Thus, predicting the risk of cancer in this population would be interesting.
NT-proBNP is mainly used in diagnosing heart failure15, although it may also predict the development of heart failure and death in patients with cardiovascular disease14, 16. In addition, it has been associated with total death in elderly subjects17-20.
In 2015 we described for the first time that NT-proBNP is an independent predictor of the appearance of malignancies in patients with CAD7. However, we hypothesized that probably NT-proBNP levels could be really a marker of subclinical tumors rather than a real predictor of the development of new cancers. To test this hypothesis we have expanded the sample size and extended the follow-up period of the same series of patients, reporting a total of 59 patients developing cancer instead of the 24 cases reported previously. Then, we divided the patients receiving a new cancer diagnosis during the follow-up into those receiving this diagnosis before and after three years. NT-proBNP was an independent predictor of developing a cancer in the first three years of follow-up, but not later.
The likelihood that concomitant heart failure may have influenced our results is very slim. First, the presence of previous heart failure was very low in the whole sample and significantly lower in patients developing a cancer in the first three years as compared with patients with no cancer at follow-up. Second, a low percentage of our patients developed heart failure during follow-up, without significant differences between the cancer and non-cancer groups. Interestingly, no patient in the group receiving a cancer diagnosis in the first three years developed heart failure during follow-up. Also, variables that may influence NT-proBNP levels, such as age, sex, hypertension, atrial fibrillation, glomerular filtration rate and body-mass index16, 21, 22 were included in the analysis, limiting the possibility that they could have influenced the results.
Natriuretic peptides are used in patients with cancer mainly as predictors of cardiac toxicity secondary to chemotherapy23. However, a potential relationship between plasma levels of these peptides and cancer itself has been suggested, and patients with cancer may have elevated BNP levels in the absence of heart failure6, 24. In patients >40 years of age with previous non-cardiac surgery, NT-proBNP levels≄125 pg/ml were independently associated with lung cancer after excluding cases with heart failure, CAD, and other conditions known to affect this biomarker25. Although natriuretic peptides have been shown to be secreted by small-cell lung cancer5, only 15% of the cases reported in this previous study, and around 17% in the present paper, had this type of cancer, suggesting that other tumors could also produce NT-proBNP. In addition, NT-proBNP was an independent predictor of survival in patients with non-Hodgkin lymphoma26. Of interest, NT-proBNP levels were associated with the involvement of two or more extranodal sites, suggesting a potential relationship with the stage of this malignancy. Similarly, increased NT-proBNP plasma levels predict the progression and worse outcome of metastatic renal carcinoma27, 28. In this regard, elevated NT-proBNP levels were reported to be associated with total mortality in patients with cancer and no previous cardiotoxic anticancer therapy who were stable from a cardiovascular point of view29.
Cancer cells may produce natriuretic peptides. Small-cell lung cancer may secrete both pro-atrial natriuretic peptide and BNP4, 5. Also, BNP is expressed in normal adrenal glands and in adrenal tumors30. NT-proBNP synthesis may be stimulated by several proinflammatory cytokines31 that, for instance, are expressed in Hodgkin lymphoma32, 33. Moreover, these cytokines may predict clinical outcome in diffuse large B-cell lymphomas34-36 and are increased in malignancies at advanced stages26.
The specific cause of the elevation of natriuretic peptide plasma levels seen in cancer has not yet been elucidated. It has been demonstrated that these peptides decrease the number of several cancer-cell types in vitro through a reduction of DNA synthesis37 and inhibition of c-Fos and c-Jun protooncogenes38. They also diminish the expression of vascular endothelial growth factor and that of its receptor VEGFR2, thus suggesting that these peptides have the potential to control vasculogenesis39. One work has shown opposite effects of natriuretic peptides on carcinogenesis depending on their concentrations40. Overall, natriuretic peptides seem to decrease the proliferation of cancer cells. Accordingly, they inhibit lung metastases and skin carcinogenesis in animal models41, 42.
Given that most data suggest an anti-cancer effect of natriuretic peptides, it is plausible that their production by cancer cells represents a negative feed-back mechanism trying to control tumor growth. Of interest, in our study, NT-proBNP was only useful in predicting tumors that were diagnosed in the first three years of follow-up, losing its predictive power beyond this time. This supports the hypothesis that NT-proBNP actually detects tumors that are present subclinically at the moment of blood extraction and which are not evident using the tools currently available in clinical practice. In that case, NT-proBNP could be useful for early detection of malignancies, as not all the cancers described in this paper have a specific biomarker to aid in diagnosis.
This work has certain limitations. 1) The inverse association between previous heart failure and future cancer must be interpreted with caution, due to the low percentage of patients with heart failure in addition to the limited number of them who developed cancer during follow-up. 2) Given the relatively low number of patients who developed cancer, these findings should be confirmed in other populations. 3) Also, given the limited number of patients who developed cancer we could not establish whether the predictive effect of NT-proBNP is restricted to some types of cancer or can be applied to any malignancy.