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 levelsā„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.