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EP-4740015-A1 - USE OF A MARKER SET FOR DETERMINING THE RISK OF AN INDIVIDUAL TO HAVE HEPATOCELLULAR CARCINOMA

EP4740015A1EP 4740015 A1EP4740015 A1EP 4740015A1EP-4740015-A1

Abstract

The present invention relates, amongst others, to the use of a marker set comprising at least two substances in an in vitro method for determining the risk of an individual to have hepatocellular carcinoma. A first of the at least two substances is chosen from a first group consisting of glutamine, proline, valine, pyruvate, glycine, glutamate, hydroxybutyrate, alanine, and formic acid, and wherein a second of the at least two substances is chosen from the first group, from a second group, or from a third group, wherein the second group consists of lactate and glucose, and wherein the third group consists of high-density lipoprotein, apolipoprotein A1, low-density lipoprotein, apolipoprotein B-48, apolipoprotein B-100, triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol.

Inventors

  • SCHIFFER, Eric
  • ROBERTSON, ANDREW
  • ROTHE, Victoria
  • EIGLSPERGER, Johannes
  • WINKLER, TORSTEN
  • DE JEL, Sebastian
  • STEINER, KERSTIN
  • STÄMMLER, Frank
  • VENZ, John
  • GRASSI, Marcello Gabriele
  • SALVI, MICHELE
  • KIANFAR, Khashayar

Assignees

  • Numares AG

Dates

Publication Date
20260513
Application Date
20240704

Claims (15)

  1. 1. Use of a marker set comprising at least two substances in an in vitro method for determining the risk of an individual to have hepatocellular carcinoma, characterized in that a first of the at least two substances is chosen from a first group consisting of glutamine, proline, valine, pyruvate, glycine, glutamate, hydroxybutyrate, alanine, and formic acid, and wherein a second of the at least two substances is chosen from the first group, from a second group, or from a third group, wherein the second group consists of lactate and glucose, and wherein the third group consists of high-density lipoprotein, apolipoprotein A1 , low-density lipoprotein, apolipoprotein B-48, apolipoprotein B-100, triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol.
  2. 2. Use according to claim 1 , characterized in that the second substance is different from glutamate if the first substance is glutamine, and in that the second substance is different from glutamine if the first substance is glutamate.
  3. 3. Use according to claim 1 or 2, characterized in that the first substance is glutamine and the second substance is proline.
  4. 4. Use according to claim 1 or 2, characterized in that the first substance is glycine and the second substance is proline.
  5. 5. Use according to claim 1 or 2, characterized in that the first substance is glycine and the second substance is valine.
  6. 6. Use according to claim 1 or 2, characterized in that the first substance is glutamine and the second substance is pyruvate.
  7. 7. Use according to claim 1 or 2, characterized in that the first substance is glutamine and the second substance is glycine.
  8. 8. Use according to claim 1 or 2, characterized in that the first substance is glutamine and the second substance is formic acid.
  9. 9. Use according to claim 1 or 2, characterized in that the first substance is alanine and the second substance is formic acid.
  10. 10. Use according to claim 1 or 2, characterized in that the first substance is glutamine and the second substance is glucose.
  11. 11. Use according to any of the preceding claims, characterized in that the marker set additionally comprises at least one of alpha-fetoprotein, alpha-fetoprotein isoform L3, and des-y-carboxyprothrombin.
  12. 12. Use according to any of the preceding claims, characterized in that the method comprises determining a stage of the hepatocellular carcinoma on a predeterminable scale.
  13. 13. Marker set comprising at least two substances for use in in-vivo diagnostics of hepatocellular carcinoma, characterized in that a first of the at least two substances is chosen from a first group consisting of glutamine, proline, valine, pyruvate, glycine, glutamate, hydroxybutyrate, alanine, and formic acid, and wherein a second of the at least two substances is chosen from the first group, from a second group, or from a third group, wherein the second group consists of lactate and glucose, and wherein the third group consists of high-density lipoprotein, apolipoprotein A1 , low-density lipoprotein, apolipoprotein B-48, apolipoprotein B-100, triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol.
  14. 14. Method for analyzing an isolated body fluid sample in vitro, comprising the following steps: a) determining the concentration of least two substances, wherein a first of the at least two substances is chosen from a first group consisting of glutamine, proline, valine, pyruvate, glycine, glutamate, hydroxybutyrate, alanine, and formic acid, and wherein a second of the at least two substances is chosen from the first group, from a second group, or from a third group, wherein the second group consists of lactate and glucose, and wherein the third group consists of high-density lipoprotein, apolipoprotein A1 , low- density lipoprotein, apolipoprotein B-48, apolipoprotein B-100, triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol in an isolated body fluid sample from an individual by analyzing the body fluid sample with a suited measuring technique, b) calculating a score from the determined concentrations, the score being indicative for determining the risk of the individual to have hepatocellular carcinoma.
  15. 15. Method according to claim 14, characterized in that calculating the score involves calculating a ratio between at least two concentration values.

Description

Use of a marker set for determining the risk of an individual to have hepatocellular carcinoma Description The present invention relates to the in-vitro use of a marker set for determining the risk of an individual to have hepatocellular carcinoma according to the preamble of claim 1 , to the further medical use of such a marker set according to the preamble of claim 13, and to an analysis method for determining the risk of an individual to have hepatocellular carcinoma according to the preamble of claim 14. Hepatocellular carcinoma (HCC) is an aggressive tumor that mainly develops in patients with chronic liver disease and cirrhosis. The malign tumor develops out of the liver tissue itself thereby counting as one of the primary liver cancer diseases. The growth ranges from solitary, multicenter, to diffuse infiltrative. Affected patients typically present with generalized symptoms such as jaundice, ascites, loss of appetite, fatigue, and mild to moderate upper abdominal pain often in late disease stages. Therefore, HCC is frequently diagnosed late in its course, due to the absence of pathognomonic symptoms (1 ). Seven out of ten diagnosed HCCs are already in the advanced stage when first diagnosed. Consequently, many patients have disease which is untreatable. Worldwide, HCC represents the fifth most common cancer and the second most common cause of cancer related deaths in men (2-4). In women, it is the seventh most diagnosed cancer and the sixth leading cause of cancer death. In some countries in Southeast Asia and Africa, it is the most common malign tumor. The number of deaths per year in HCC is virtually identical to the incidence throughout the world, underscoring the high case fatality rate of this aggressive disease (5). The 5-year survival of patients with HCC is only 0 to 10 % when the tumor is diagnosed in an advanced stage (6). In contrast, 5-year survival rates of 50 to 70 % are possible when the tumor is diagnosed at an early stage, for which more curative therapies are available. Thus, the central goal of HCC surveillance programs is to detect HCC tumors as early as possible to be able to provide curative treatments and improve patient outcomes. There is evidence that surveillance programs can reduce HCC related mortality by 37 % (7). Guidelines recommend enrolment of patients at risk, i.e., patients with liver cirrhosis or chronic hepatitis B, into regular surveillance programs. All guidelines recommend abdominal ultrasound every six months as the method of choice for HCC surveillance, but they differ in their recommendations regarding the use of the tumor biomarker alpha-fetoprotein (AFP) (8- 10). In 2009, a meta-analysis including 13 studies showed that the most widely used surveillance test, abdominal ultrasound, is able to detect HCC with a sensitivity and specificity of 94 % before tumors present with clinical symptoms (1 1 ). However, the sensitivity of ultrasound for detecting early-stage HCC was only 63 %. A more recent meta-analysis confirmed the suboptimal performance of ultrasound for early HCC detection with a sensitivity of less than 50 % (12). A major drawback of ultrasound in HCC surveillance is that its performance in detecting early HCC highly depends on the expertise of the operator and the quality of the equipment. AFP is the most widely tested biomarker in HCC, however, as a serological test for surveillance, AFP has a suboptimal performance. One reason is that only a small proportion of tumors at an early stage (10-20 %) present with abnormal AFP serum levels (13-15). The combination of ultrasound and AFP hardly increased sensitivity for early HCC compared to ultrasound alone (69 % vs. 63 %) in one meta-analysis, while a more recent meta-analysis suggests that AFP may significantly improve sensitivity for early HCC detection (50 % vs. 63 %) for early HCC detection (11 , 12). Other proposed serum biomarkers, such as AFP-L3 (an isoform of AFP) and DCP (des-y- carboxyprothrombin), are markers of advanced tumor stage and their performances, despite being more sensitive than AFP, are not optimal for the detection of early HCC (16-20). Recently, a statistical model evaluating above mentioned biomarkers together with age and sex of the patient was developed to improve detection of HCC in patients with chronic liver disease, and was named GALAD based on its input variables: Gender, Age, AFP-L3, AFP, des-y-carboxy-prothrombin (21 ). The GALAD score was validated across several cohorts from Germany, UK, Japan, Hong Kong, and the U.S., showing high accuracy in detecting HCC with sensitivities greater 90 % (22-24). Despite these very promising results, the GALAD score and its modifications are not yet recommended by clinical guidelines and still warrant extensive validation of their utility in prospective studies and clinical routine. Taken together, there is still a substantial clinical need for biomarkers to complement ultrasound in the detection of HCC, in particular early HCC