Chromogranin A as Blood Marker in Cancer Patients

A general characteristic for neuroendocrine tumors (NET) is expression of chromogranin A
(CgA), which is released from neuroendocrine cells, occasionally together with cell specific
hormones such as gastrin, insulin, somatostatin, and serotonin in functional tumors. Human
CgA is an acidic 439 amino acid protein with a sequence containing several mono- and dibasic
cleavage sites, and correspondingly, numerous fragments of CgA have been identified in tissue
and plasma. CgA is critical to the formation of secretory granules that characterize NETs,
and is therefore a useful marker for NETs.

Plasma concentrations of CgA and/or CgA fragments are elevated in most NETs. Moreover, since
plasma CgA concentrations seem to be closely related to tumor burden in humans, plasma CgA
concentration is an important prognostic factor. As such, high plasma concentrations of CgA
as well as a dramatic increase in plasma CgA within a short time period, is associated with a
poorer prognosis. Plasma CgA has also been suggested to be useful in the follow-up of
patients with NETs.

Taken together, these observations support the notion that CgA is a promising biomarker
candidate for monitoring treatment effectiveness and disease progression or regression.

Participation in this clinical study requires no additional visits to the oncologist,
radiology or the laboratory. All information needed for the study will be obtained during
typical visits as recommended by the oncologist. Clinical assessment of patients with
GEP-NETs (according to NCCN guidelines) is based on physical exam, imaging (CT or MRI scans)
and laboratory parameters. The course of disease is followed by RECIST 1.1 categorization
including the evaluation of tumor burden by imaging.

Inclusion Criteria:

- Primary well-differentiated G1 and G2 neuroendocrine tumor located in jejunum, ileum,
colon, rectum, duodenum, appendix, stomach, or pancreas

- Measurable disease according to RECIST criteria (Version 1.1)

- Eighteen years of age or older

- CT or MRI order obtained and within 4 weeks of CgA measurement

- BRAHMS CgA II KRYPTOR baseline measurement available

- Patient has discontinued the following treatments for at least 3 weeks before study
start: i) proton pump Inhibitors (PPI), ii) corticoids, iii) H2-receptor antagonists

- Baseline Eastern Cooperative Oncology Group Performance Scale (ECOG PS) <2

- Written informed consent signed

Exclusion Criteria:

- Other active malignancy with the exclusion of melanoma or other cancers that occurred
more than 5 years ago

- Participation in another clinical trial involving an investigational therapeutic
(exception: diagnostic studies and studies evaluating known therapies)

- No measurable disease by RECIST criteria (Version 1.1)

- Severe renal dysfunction defined as creatinine of 1.5x upper limit of normal (ULN)

- Severe liver dysfunction in the absence of liver metastasis defined by aspartate
aminotransferase (AST), serum total bilirubin and/or alanine transaminase (ALT) 1.5x
ULN; severe liver dysfunction in the presence of liver metastasis defined by AST and
ALT over 5x ULN and total bilirubin over 1.5x ULN

- Severe gastrointestinal disorders (chronic atrophic gastritis, pancreatitis,
inflammatory bowel disease, irritable bowel syndrome)

- Severe cardiovascular disease (severe symptomatic congestive heart failure, pulmonary
artery hypertension, acute coronary syndrome)

- Patients receiving active treatment with the following medications and samples were
collected less than 3 weeks after discontinuing: i) proton pump Inhibitors (PPI), ii)
corticoids, iii) H2-receptor antagonists

- Chronic alcohol and/or substance abuse

- Known pregnancy