Page 78 - Read Online

HOW TO AVOID MISINTERPRETATION better when compared to CgA (93-98% vs. 50-80%) [53,54]
OF CGA, GASTRIN AND U-5HIAA IN exceeding the performance criteria proposed by an expert
CLINICAL PRACTICE? panel convened to evaluate NET biomarkers. MAAAs and
NETest in particular may improve diagnostic accuracy
There are many conditions that interfere with CgA and and offer better interdisciplinary perspective than single
u-5HIAA measurements. For CgA there is no universally analyte testing.
accepted CgA assay and the different methodologies can
lead to confusing results. Many physiological conditions IS THERE A CLINICAL ROLE FOR NOVEL
as stress, pregnancy or exercise can increase circulating BIOMARKERS?
CgA levels and the same is true for many drugs and non-
neuroendocrine diseases. U-5HIAA measurements also Recently, several novel biomarkers for NETs have
have inherent pitfalls since they require a 24 h urine been developed using an integration of genomics and
collection and are subject to interference by dietary technology platforms. In addition to gene transcript by
habits. [2,5,8,9,13-15,29,31,33] Tables 2 and 3 show the most MAAAs, circulating tumor cell (CTC) and microRNA
important pitfalls and bottlenecks and possible remedies (miRNA) analyses have been proposed. [12]
in CgA, gastrin and u-5HIAA interpretation and provide
[55]
suggestions to reduce interference in circulating biomarker Khan et al. showed that the number of CTC detected
measurements for more accurate tumor management. in patients with neuroendocrine tumors was comparable
to other tumors in which CTC have been shown to have
MONOANALYTE OR MULTIANALYTES? prognostic relevance. In this study, 47% of patients with
midgut (n = 101) and 24% of patients with pancreatic (n
The identification of effective biomarkers in patients with = 42) tumors had ≥ two CTC detected. Presence of CTC
NETs is a high priority. In a recent Delphi consensus, was clearly associated with increasing tumor burden
the panel of neuroendocrine experts agreed that an and weakly with tumor grade. In a more recent, large
acceptable standard for a diagnostic biomarker should prospective study, the same group demonstrated that
have a sensitivity of at least 80%, specificity of at least changes in CTC were associated with response to treatment
90%, and positive and negative predictive values of each and overall survival in metastatic neuroendocrine tumors,
at 80% or more. In addition, the biomarker should be suggesting CTC may be useful as a surrogate marker
[12]
able to provide information regarding the proliferative to direct clinical decision making. Although there
[56]
and metastatic capacity of a tumor, the identification is an increasing interest in CTC as a biomarker, recent
of surgical and medical treatment effectiveness and consensus concluded that CTC analyses have several
correlate with patient survival. Unfortunately current technical limitations and need further validation before
universal circulating biomarkers are not able to provide being adopted into routine clinical practice. [12]
this standard and, in particular, the role of CgA in the
diagnosis of neuroendocrine tumors is decreasing. There is also increasing interest in miRNAs as clinical
biomarkers of tumorigenesis, treatment response and
The principal limitation in the measurement of outcomes, but to date clinical data are scarce and clinical
circulating CgA is the absence of a gold standard application challenging. Similarly, there are several novel
assay and wide variability of results from different monoanalyte assays (i.e. connective tissue growth factor
kits and laboratories. In addition, false positive results for carcinoid heart disease (CCN2) or paraneoplastic Ma
are reported as a result of other neoplasia (prostate antigen 2 (PNMA2) for small intestinal neuroendocrine
and breast cancer and hepatocellular carcinoma) and tumors, but these analyses are not available in clinical
common conditions (kidney, liver or heart failure, chronic practice. [12] Further, panelists of the recent Delphi
gastritis, inflammatory bowel disease, PPI use, essential consensus gave the strongest support to the use of
hypertension and physical stress). In addition, the current emerging biomarkers in multianalyte technology based
biomarkers used for gastroenteropancreatic NETs are on genomics. [12]
inadequate for bronchopulmonary NETs and vice versa.
For these reasons, a multianalyte approach would likely CONCLUSION
be more effective compared to a monoanalyte circulating
biomarker. To this end, a specific multianalyte assay with To date, the identification of sensitive, specific and
algorithmic analyses (MAAA) named NETest has recently reproducible NET circulating biomarkers for the
been developed. NETest is a PCR-based, 51-transcript prediction, diagnosis, prognosis and classification of
signature that is based on correlating and normalizing NETs and to evaluate changes during therapy has been
[12]
multiple sets of variables that represent gene clusters limited and remains an unfulfilled unmet medical need
specific to NETs and their biological behavior. The use as defined by the 2007 National Cancer Institute NET
of this blood-based test is proposed to facilitate early meeting. There are no specific circulating monoanalyte
[57]
detection of disease recurrence and to predict therapeutic biomarkers for neuroendocrine tumors that fulfill the
efficacy. The diagnostic performance of MAAAs was NIH recommended criteria and the search continues for
354
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 31, 2016 ¦