Methods for testing sensitivity to multi-kinase inhibitors

Abstract

To provide appropriate treatment for liver cancer patients, we offer indicators of sensitivity to multi-kinase inhibitors. [Solution] The present invention provides a testing method, testing apparatus, and testing program that use the fat content in liver cancer tissue as an indicator of sensitivity to multi-kinase inhibitors. This makes it possible to predict the therapeutic effect of multi-kinase inhibitors and provide appropriate treatment to individual liver cancer patients. The fat content can be calculated from images of liver cancer tissue or signals for image display. Images include MRI images, CT images, ultrasound images, stained images of tissue biopsies, etc. Signals for image display include MR signals, etc. Examples of multi-kinase inhibitors include lenvatinib and sorafenib.

Description

[Technical Field]

[0001] This invention relates to a method, apparatus, and program for testing sensitivity to multi-kinase inhibitors. [Background technology]

[0002] Liver cancer is the fourth leading cause of cancer-related death worldwide. Hepatocellular carcinoma (HMCC) is the most common type of primary liver cancer and is a heterogeneous disease with various etiologies. In recent years, the prevalence of nonviral HMCC has been rapidly increasing, with various causes including heavy alcohol consumption, non-alcoholic fatty liver disease (NAFLD), and diabetes. Immunotherapy with immune checkpoint inhibitors and molecular targeted drugs are standard treatments for advanced HMCC, but the effectiveness of each drug is still limited. Currently in Japan, combination therapy with atezolizumab and bevacizumab is the first-line treatment for advanced HMCC, with sorafenib and lenvatinib being the second-line treatments. However, many patients do not achieve therapeutic effects with their chosen drug. On the other hand, if the chosen drug is ineffective, the treatment method is changed, such as by switching drugs, but repeated changes gradually reduce liver function. Therefore, it is important to select the appropriate drug for each patient. The inventors have reported that fatty hepatocellular carcinoma has an immune-rich but immune-exhausted cancer microenvironment, and that the fat content in liver cancer tissue serves as an indicator of sensitivity to immune checkpoint inhibitors (Non-Patent Document 1, Patent Document 1).

[0003] Receptor tyrosine kinases are important molecules involved in intracellular signaling pathways such as cell proliferation. Receptor tyrosine kinases have been reported to play a crucial role in tumor development and progression. Numerous molecularly targeted drugs that inhibit receptor tyrosine kinases and their ligands have been developed, and excellent therapeutic effects have been reported. These molecularly targeted drugs include monoclonal antibodies and small molecule compounds. Small molecule compounds that inhibit vascular endothelial growth factor receptor (VEGFR), one of the receptor tyrosine kinases, are called multi-kinase inhibitors because they also inhibit other kinases in addition to VEGFR. [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] WO2023 / 210752A1 [Non-patent literature]

[0005] [Non-Patent Document 1] MURAI, H. et al. Hepatology. 14 May 2022, vol. 77, pp. 77-91. [Overview of the project] [Problems that the invention aims to solve]

[0006] The present inventors aimed to provide an indicator of sensitivity to multi-kinase inhibitors in order to provide appropriate drugs to each patient in the drug therapy of liver cancer. [Means for solving the problem]

[0007] The inventors of this invention have discovered that liver cancer with a high fat content is resistant to drug therapy using multi-kinase inhibitors, while liver cancer with a low fat content is susceptible, and have completed the present invention.

[0008] In other words, the present invention consists of the following: 1. A method for testing sensitivity to a multi-kinase inhibitor, comprising the step of measuring the fat content in liver cancer tissue. 2. The method according to paragraph 1, wherein the fat content is calculated from an image obtained from liver cancer tissue or a signal for displaying an image obtained from liver cancer tissue. 3. The fat content is calculated from the signal for image display obtained from liver cancer tissue, according to the method described in paragraph 2 above. 4. The method according to item 3 above, wherein the signal for displaying the image is an MR signal. 5. The method according to any one of paragraphs 1 to 4, further comprising the step of comparing the fat content with a reference value, wherein if the fat content is less than the reference value, it is determined that the person is sensitive to a multi-kinase inhibitor. 6. The method described in item 5 above, wherein the reference value is selected from the range of 5% to 15%. 7. The method described in paragraph 6 above, wherein the reference value is 10%. 8. The method according to any one of items 1 to 7 above, wherein the multikinase inhibitor is lenvatinib or sorafenib. 9. The method according to any one of items 1 to 7 above, wherein the liver cancer is hepatocellular carcinoma. 10. A device for testing sensitivity to multi-kinase inhibitors, (a) A fat content calculation unit that calculates the fat content in liver cancer tissue from the MR signal of liver cancer tissue, and (b) Output unit that compares the calculated fat content with the reference value and indicates the sensitivity level to the multi-kinase inhibitor. A device equipped with; a device. 11. A program for testing sensitivity to multi-kinase inhibitors, (c) Process of inputting MR signal data of liver cancer tissue, (d) A step of calculating the fat content in liver cancer tissue from the input MR signal data, and (e) A process of comparing the calculated fat content with the reference value and outputting the sensitivity level. A program that executes something.

Advantages of the Invention

[0009] The present invention enables prediction of the therapeutic effect of a multi-kinase inhibitor and allows selection of a drug suitable for an individual liver cancer patient.

[0010] Since many liver cancer patients undergo imaging diagnosis without undergoing tumor biopsy in general medical treatment, the method, apparatus, and program of the present invention are easy to clinically apply. In addition, the inspection method of the present invention is a method with less burden on patients.

Brief Description of the Drawings

[0011] [Figure 1] FIG. 1 shows the treatment responsiveness of lenvatinib. It shows the Kaplan-Meier analysis results of the progression-free survival period of patients stratified by the presence or absence of fatty change in hepatocellular carcinoma. In the figure, Fat(+) means fatty hepatocellular carcinoma, and Fat(-) means non-fatty hepatocellular carcinoma. Patients with non-fatty hepatocellular carcinoma showed a significantly longer progression-free survival period (PFS) than patients with fatty hepatocellular carcinoma (P = 0.011). Statistical analysis was performed by the log-rank test. [Figure 2] FIG. 2 shows the disease control rate (DCR) of lenvatinib in patients stratified by the presence or absence of fatty change. [Figure 3] FIG. 3 shows the fat content rate of 20 hepatocellular carcinoma patients. It shows the correlation between the fat content rate (the ratio of the number of fat droplet-containing cells, fatty change rate) in the HE staining image of hepatocellular carcinoma and the fat content rate (FFCSI) calculated from the MR signal. The correlation was evaluated using Pearson's product-moment correlation coefficient.

Modes for Carrying Out the Invention

[0012] The present invention relates to a method for testing sensitivity to a multi-kinase inhibitor, a testing apparatus, and a testing program.

[0013] In the present invention, a multi-kinase inhibitor is a compound that inhibits the tyrosine kinase activity of the vascular endothelial growth factor receptor (VEGFR). The multi-kinase inhibitor in the present invention is a small molecule compound that has inhibitory activity not only against VEGFR but also against other kinases. The multi-kinase inhibitor in the present invention does not include monoclonal antibodies. The multi-kinase inhibitors whose sensitivity can be evaluated by the testing method of the present invention are not particularly limited, and examples include lenvatinib, sorafenib, regorafenib, cabozantinib, etc. Preferred multi-kinase inhibitors include lenvatinib and sorafenib, and more preferably lenvatinib.

[0014] The liver cancers targeted by the testing method of the present invention include metastatic liver cancer and primary liver cancer, preferably primary liver cancers such as hepatocellular carcinoma and cholangiocarcinoma, and more preferably hepatocellular carcinoma.

[0015] Sensitivity to multi-kinase inhibitors can be rephrased as reactivity or responsiveness to multi-kinase inhibitors. It can also be rephrased as sensitivity to drug therapy with multi-kinase inhibitors. While drug therapy with multi-kinase inhibitors is used for many liver cancer patients, not all patients achieve the same effect; some patients are highly sensitive, while others are not. Furthermore, some patients develop resistance later, even if a therapeutic effect is initially observed. Sensitivity to multi-kinase inhibitors can be tested before or during treatment. If sensitivity is found through testing, a good anti-cancer effect can be obtained by starting or continuing administration of multi-kinase inhibitors. If insensitivity is found through testing, other drugs or other treatment methods can be selected. In this way, it is possible to provide patients with appropriate treatment methods and continue treatment without reducing liver function.

[0016] The present invention provides a testing method that uses fat content as an indicator (biomarker) of sensitivity to multi-kinase inhibitors, and is characterized by including a step of measuring the fat content in liver cancer tissue. There are no particular limitations on the method for measuring the fat content in liver cancer tissue. Preferably, the fat content of the present invention is calculated from an image obtained from liver cancer tissue or a signal for image display obtained from liver cancer tissue. Images include medical images such as MRI images, CT images, ultrasound images, stained images of tissue biopsies, and pathological tissue images. Signals for image display include signals for displaying medical images such as MRI images, CT images, ultrasound images, stained images of tissue biopsies, and pathological tissue images. Specific examples of signals for image display include MR signals in MRI, echo signals in ultrasound examinations, and signals obtained from X-rays in CT examinations, with MR signals being a more preferred signal for image display.

[0017] In the present invention, an MRI image is an image obtained by magnetic resonance imaging (MRI), and is preferably a chemical shift imaging image. In the present invention, a chemical shift imaging image is an image obtained by chemical shift imaging.

[0018] Known methods can be used to obtain images or signals for image display from liver cancer tissue, such as abdominal MRI, abdominal CT (computed tomography), abdominal ultrasound, and HE staining of liver biopsy tissue sections.

[0019] In the present invention, "liver cancer tissue" refers to tumor tissue in the liver, and is not particularly limited as long as it can be used as a subject for testing for sensitivity to multi-kinase inhibitors, but preferably it is tumor tissue in the liver of a patient who has liver cancer or is suspected of having liver cancer.

[0020] The subjects of the examination are not particularly limited, but preferably humans and pets, and more preferably humans.

[0021] The term "cancer tissue" or "tumor tissue" refers to tissue containing at least one tumor cell, and may include connective tissue and blood vessels that support the tumor.

[0022] The fat content in this invention is not particularly limited as long as it is an indicator showing the proportion of fat in liver cancer tissue. For example, the fat content may be the proportion of fat in the entire liver cancer tissue, or it may be the proportion of fat measured, calculated, or estimated in a two-dimensional or three-dimensional region of a part of the liver cancer tissue. The fat content may be the ratio of cells having lipid droplets to the total number of cells in the liver cancer tissue (the ratio of cells with lipid droplets, hereinafter also referred to as the steatosis rate). The fat content may also be the ratio of the area or volume of lipid droplets obtained from an image of the liver cancer tissue. Furthermore, the fat content may be the proportion of fatty components in the liver cancer tissue.

[0023] Fat content can be calculated from images obtained from liver cancer tissue. Specific examples of fat content include the percentage of cells containing lipid droplets in an image, the percentage of fat area in an image, and, more specifically, the percentage of lipid droplet-containing cells in a stained tissue image.

[0024] Fat content can be calculated from signals obtained for image display from liver cancer tissue. A specific example of fat content is the fat content calculated from MRI signals. A more specific example is the fat content calculated by decomposing the net MRI signal intensity into fat signal intensity and water signal intensity, and then dividing the result by (fat signal intensity + water signal intensity).

[0025] The method for obtaining an image to measure the fat content in the inspection method of the present invention is not particularly limited. Either an invasive or non-invasive method may be used, but a non-invasive method is preferred because many patients with unresectable advanced liver cancer who are candidates for drug therapy with multi-kinase inhibitors are diagnosed and treated without tumor biopsy. An invasive method is, for example, tissue biopsy. Specifically, it can be quantified by the ratio of cells containing large lipid droplets in the stained image of liver cancer tissue biopsy. A non-invasive method is not particularly limited, and for example, MRI, CT, ultrasound, etc. can be used, with MRI being more preferred from the viewpoint of detection accuracy.

[0026] Methods for measuring fat content using MRI include existing methods such as proton nuclear magnetic resonance spectroscopy ( 1 The following methods can be applied: H-MRS, 3-point Dixon (DIXON), multi-echo gradient-echo (MEGE), chemical shift imaging, and frequency-selective imaging (Magn Reson Med Sci. 2011; 10(1): 41-8; Radiographics. 2009 Jan - Feb; 29(1): 231-60.). A preferred method for measuring fat content is the method using chemical shift imaging (CSI). More preferably, the fat content is expressed by the following formula (1), which is the fat fraction measured by CSI (FF). CSI It can be calculated based on the intensities of the water signal and fat signal decomposed from the MR signal, and more specifically, it can be calculated from the ratio of the fat signal intensity to the sum of the fat signal intensity and water signal intensity.

[0027]

number

[0028] In formula (1), “S fat " is the signal intensity of fat, "Swater " represents the signal strength of water. Equation (1) can be converted to the following equation (2).

[0029] In equation (2), the fat content can be calculated from the signal intensity in the common region of interest (ROI) of the in-phase and opposed-phase images of the MR signal frequency obtained from the protons of water molecules and the protons of the methylene groups of fat molecules. Specifically, a region of interest can be set on the tumor tissue in the MRI image, preferably the whole or a part of the tumor tissue in the MRI image, more preferably the whole of the tumor tissue in the MRI image, and the average signal intensity of the region of interest in the in-phase image is taken as IP, and the average signal intensity of the region of interest in the opposed-phase image is taken as OP, and this can be applied to equation (2). The part of the tumor tissue is not particularly limited, but for example, it could be 1 mm within the contour of the tumor tissue. 2 ~10000mm 2 Preferably 20 mm 2 ~1000mm 2 This may be a region having a certain area. In defining the region of interest, tumor tissue can be identified using MRI images enhanced with a contrast agent. The contrast agent used to identify tumor tissue is not particularly limited as long as it is available for the detection of liver cancer, and examples include sodium gadoxetate (Gd-EOB-DTPA) and super paramagnetic iron oxide (SPIO). A preferred contrast agent is sodium gadoxetate (Gd-EOB-DTPA).

[0030]

number

[0031] In equation (2), "IP" represents the in-phase intensity expressed in equation (3), and "OP" represents the opposite-phase intensity expressed in equation (4) (Radiographics. 2009J an-Feb; 29(1): 231-60.).

[0032] [Mathematics]

[0033] In formula (3), "S water " represents the signal intensity of water, and "S fat " represents the signal intensity of fat.

[0034] [Mathematics]

[0035] In formula (4), "S water " represents the signal intensity of water, and "S fat " represents the signal intensity of fat.

[0036] The inspection method of the present invention can further include a step of comparing the fat content rate with a reference value. The inspection method of the present invention can determine the sensitivity level to a multi-kinase inhibitor by comparing the measured fat content rate with a preset reference value. The sensitivity level can be the presence or absence of sensitivity. When there is sensitivity, it can be expressed as "sensitive", and when there is no sensitivity, it can be expressed as "resistant". Other examples of the sensitivity level include, for example, high sensitivity, medium sensitivity, low sensitivity, etc. The sensitivity level can also be represented numerically in stages, for example, it can be set as sensitivity level 1, sensitivity level 2, etc. For example, when the calculated fat content rate is less than the preset reference value, it can be determined that it is sensitive to the multi-kinase inhibitor. When the calculated fat content rate is equal to or greater than the preset reference value, it can be determined that it is resistant to the multi-kinase inhibitor.

[0037] The aforementioned reference value can be selected from a range of 1% to 40%, for example, 40%, 30%, 25%, 20%, 17%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, and 1%. Preferably, it can be selected from a range of 3% to 20%, more preferably 5% to 15%, and even more preferably 5% to 10%.

[0038] Reference values ​​for fat content can be set for each method of measuring fat content. Sensitivity to multi-kinase inhibitors can be determined by comparing the reference values ​​for each method of measuring fat content with the actual fat content. Below are reference values ​​for steatosis rate (the ratio of cells with lipid droplets to the total number of cells in liver cancer tissue (the ratio of cells with lipid droplets)) and fat content FF measured by chemical shift imaging. CSI Further explanation will be provided regarding the setting of reference values ​​in (%).

[0039] The reference value for the fatification rate can be selected from the range of 1% to 40%, for example, 40%, 30%, 25%, 20%, 17%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, and 1%. Preferably, it can be selected from the range of 3% to 15%, more preferably from 4% to 10%, and even more preferably from 5%.

[0040] Fat content FF measured by chemical shift imaging CSI The reference value in (%) can be selected from a range of 3% to 40%, for example, 40%, 30%, 25%, 20%, 17%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, and 3%. Preferably, it can be selected from a range of 5% to 20%, more preferably 5% to 15%, even more preferably 8% to 12%, and most preferably 10%.

[0041] FF CSI(%) has a strong positive correlation with the fat content rate. Therefore, the fat content rate FF CSI The reference value for (%) and the reference value for the fat conversion rate mentioned above may be the same.

[0042] (Device for testing sensitivity to multi-kinase inhibitors) The apparatus for testing sensitivity to multi-kinase inhibitors according to the present invention comprises the following configurations (a) and (b). (a) Fat content calculation unit that calculates the fat content in liver cancer tissue from the MR signal of liver cancer tissue. (b) Output unit that compares the calculated fat content with the reference value and indicates the sensitivity level to the multi-kinase inhibitor.

[0043] The detection unit for detecting the MR signal of liver cancer tissue may be provided in the inspection device of the present invention or in an external device. The signal detection unit provided in the device of the present invention or in an external device detects the MR signal generated by the nuclear magnetic resonance phenomenon. The detected MR signal is transmitted as signal data to the fat content calculation unit of the device of the present invention by known data transmission and reception means. The fat content calculation unit calculates the fat content from the MR signal of the liver cancer tissue detected by the signal detection unit. A preferred calculation method is to decompose the net MR signal into a water signal and a fat signal, and calculate the fat content from the fat signal intensity relative to the sum of the fat signal intensity and the water signal intensity. The output unit of the device of the present invention compares the fat content calculated by the fat content calculation unit with a preset reference value and indicates the sensitivity level to the multi-kinase inhibitor according to the comparison result. The sensitivity level may be either sensitivity or not, or it may be quantified or stratified as a sensitivity level according to the level of fat content.

[0044] The inspection device of the present invention may be a device connected to a known MRI device, or it may be a device integrated with an MRI device. When the inspection device of the present invention is a device connected to an MRI device, the signal detection unit is provided in the MRI device, and the fat content calculation unit and output unit are provided in the inspection device of the present invention. The fat content calculation unit and output unit of the inspection device of the present invention may be provided in a computer equipped with a CPU and a storage medium, etc. Embodiments of each configuration of the inspection device of the present invention are the same as those of the embodiment described in the inspection method above.

[0045] (Program for testing sensitivity to multi-kinase inhibitors) The program for testing sensitivity to multikinase inhibitors of the present invention performs the following steps (c), (d), and (e). (c) Process of inputting MR signal data of liver cancer tissue (d) A process for calculating the fat content in liver cancer tissue from the input MR signal data. (e) A process of comparing the calculated fat content with the reference value and outputting the sensitivity level.

[0046] The process of inputting MR signal data involves inputting MR signal data generated by the nuclear magnetic resonance phenomenon. The process of calculating fat content involves calculating the fat content from the input MR signal data. A preferred calculation method involves decomposing the net MR signal data into water signal data and fat signal data, and calculating the fat content from the fat signal intensity relative to the sum of the fat signal intensity and water signal intensity. The process of outputting the sensitivity level involves comparing the calculated fat content with a preset reference value and outputting the sensitivity level to the multi-kinase inhibitor according to the comparison result.

[0047] By installing the testing program of the present invention into an MRI device and / or a device externally connected thereto, sensitivity to multi-kinase inhibitors can be tested. Embodiments of each configuration of the testing program of the present invention are the same as those described in the embodiments of the testing method and testing device. [Examples]

[0048] The present invention will be specifically described below with reference to examples to deepen understanding of the invention, but these examples are not intended to limit the scope of the invention. The following tests were conducted in accordance with the principles of the Declaration of Helsinki, approved by the Ethics Committee of Osaka University Hospital, and with the consent of all patients.

[0049] (Example 1) Evaluation of therapeutic response to multikinase inhibitors

[0050] Between October 2020 and September 2021, lenvatinib-based drug therapy was administered for hepatocellular carcinoma (HCC) at Osaka University Hospital and six affiliated hospitals. Thirty-nine patients who underwent abdominal MRI examinations, including chemo-shift imaging (CSI), prior to the initiation of drug therapy were retrospectively enrolled. Enrollment criteria included patients with measurable lesions in the liver, patients without significant iron deposition in the liver, and patients who had undergone evaluation of the initial treatment response. The signal intensity of the largest tumor in each patient was obtained by plotting a region of interest (ROI) from in-phase and out-of-phase images at the same level. ROI plotting was performed manually by drawing the tumor contour using Horos® software (Nimble Co LLC, d / b / a Purview). Fat fraction measured by CSI (FF) was also used. CSI ) was calculated using the following formula (2).

[0051]

number

[0052] FF CSI The study defined tumors accounting for more than 10% as steatotic hepatocellular carcinoma. As a result, 6 out of 39 patients were classified as having steatotic hepatocellular carcinoma. There were no significant differences in clinical characteristics between steatotic hepatocellular carcinoma and non-steatotic hepatocellular carcinoma.

[0053] During lenvatinib therapy, dynamic contrast-enhanced CT scans were performed every six weeks to evaluate treatment response. Treatment response was assessed using the mRECIST criteria (modified Response Evaluation Criteria in Solid Tumors).

[0054] Patients with non-steatotic hepatocellular carcinoma (HMCC) showed significantly longer progression-free survival (PFS) than patients with steatotic HMCC (Figure 1). Furthermore, patients with non-steatotic HMCC had a higher disease control rate (DCR) than patients with steatotic HMCC (Figure 2). Specifically, FF before initiation of lenvatinib therapy... CSI In patients with a 10% or lower FF rate, the DCR {(CR+PR+SD) / (CR+PR+SD+PD)} was 80%, indicating that treatment was effective in many patients. On the other hand, FF before initiating lenvatinib therapy... CSI In patients with a prevalence of 10% or more, the disease complete response (DCR) was 50%, indicating that half of the patients did not achieve sufficient therapeutic effect. The determination of CR, PR, and SD in disease control rates represents the best therapeutic effect after the start of treatment.

[0055] (Example 2) Measurement of fat content using pathological tissue images

[0056] Tissue samples of hepatocellular carcinoma (HCC) surgically resected from 20 patients were stained with hematoxylin and eosin (HE), and the number of lipid droplet-containing cells was measured. The ratio of lipid droplet-containing cells to the total number of cells in the hepatocellular carcinoma tissue was calculated as the lipid content rate (steatosis rate, histological lipid accumulation) (Figure 3).

[0057] (Example 3) Measurement of fat content of hepatocellular carcinoma by MRI

[0058] The 20 HCC patients described in Example 2 underwent abdominal MRI examinations, including chemoshift imaging (CSI), prior to cancer tissue resection surgery. The signal intensity of the largest tumor in each patient was obtained by plotting a region of interest (ROI) from in-phase and out-of-phase images at the same level. ROI plotting was performed manually by drawing the tumor contour using Horos® software (Nimble Co LLC, d / b / a Purview). Fat fraction measured by CSI (FF) was also measured. CSI The value was calculated using the above formula (2). It was determined that hepatocellular carcinoma with a fat content of 10% or more in 5 patients was resistant to multi-kinase inhibitor drug therapy, while hepatocellular carcinoma with a fat content of less than 10% was sensitive to multi-kinase inhibitor drug therapy (Figure 3).

[0059] Fattyness rate measured by pathological tissue imaging and FF measured by chemical shift imaging. CSI A strong positive correlation was observed between the two (Figure 3).

[0060] These results clearly show that steatotic hepatocellular carcinoma is resistant to multi-kinase inhibitor therapy, while non-steatotic hepatocellular carcinoma is sensitive. The intratumoral fat content suggests that it could be a novel biomarker for predicting the effectiveness of multi-kinase inhibitor therapy in hepatocellular carcinoma. [Industrial applicability]

[0061] To predict the effectiveness of multi-kinase inhibitor drug therapy in liver cancer patients and provide appropriate treatment.

Claims

1. A method for testing sensitivity to multi-kinase inhibitors, comprising the step of measuring the fat content in liver cancer tissue.

2. The method according to claim 1, wherein the fat content is calculated from an image obtained from liver cancer tissue or a signal for displaying an image obtained from liver cancer tissue.

3. The method according to claim 2, wherein the fat content is calculated from an image display signal obtained from liver cancer tissue.

4. The method according to claim 3, wherein the signal for displaying the image is an MR signal.

5. The method according to any one of claims 1 to 4, further comprising the step of comparing the fat content with a reference value, wherein if the fat content is less than the reference value, it is determined that the person is sensitive to a multi-kinase inhibitor.

6. The method according to claim 5, wherein the reference value is a value selected from the range of 5% to 15%.

7. The method according to claim 6, wherein the reference value is 10%.

8. The method according to any one of claims 1 to 4, wherein the multi-kinase inhibitor is lenvatinib or sorafenib.

9. The method according to any one of claims 1 to 4, wherein the liver cancer is hepatocellular carcinoma.

10. A device for testing sensitivity to multi-kinase inhibitors, A fat content calculation unit that calculates the fat content in liver cancer tissue from the MR signal of liver cancer tissue, and The output unit compares the calculated fat content with the reference value and indicates the sensitivity level to the multi-kinase inhibitor. A device equipped with; a device.

11. A program for testing sensitivity to multi-kinase inhibitors, The process of inputting MR signal data from liver cancer tissue. A process for calculating the fat content in liver cancer tissue from input MR signal data, and The process involves comparing the calculated fat content with the reference value and outputting the sensitivity level. A program that executes something.

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