Gastric cancer patient with MET amplification treated with crizotinib achieves long-term survival: a case report

Introduction

Based on the Global Cancer Statistics in 2018, gastric cancer (GC) is one of the most common digestive tract tumors, ranking fifth in cancer incidence worldwide. Additionally, GC is the third most common cancer leading to cancer-related deaths (1). According to the data from 2020, approximately 1.1 million individuals diagnosed with GC each year and 770,000 died from it (2). In general, the overall survival (OS) time of progressive GC patients is generally less than 12 months, and the five-year survival rate is less than 10% (3,4). As a highly heterogeneous tumor, advanced GC patients have been mainly treated with systemic chemotherapy in the past, but the efficacy of chemotherapy was still not satisfactory. Immunotherapy has recently become a promising treatment method, but the clinical results related to immune checkpoint inhibitors (ICIs) show that the clinical efficacy of a single agent is minimal. Clinical trials are currently exploring combination therapies, mainly chemotherapy (5). In recent years, the emerging of targeted therapy improved the survival and prognosis of GC patients.

As a member of the receptor tyrosine kinases (RTKs), hepatocyte growth factor receptor (MET) plays an important role in regulating tumor proliferation, differentiation, metastasis and survival. MET gene abnormalities occur in solid tumors such as lung, liver, stomach, breast, brain and colorectal cancers (6). MET amplification, having a poor prognosis, accounts for about 4–6% of GC patients (7). Up to now, the National Comprehensive Cancer Network (NCCN) guidelines have no therapeutic agents are recommended for MET amplification in GC (8). It has been reported that crizotinib (9), savolitinib (10,11) and cabozantinib (12) have shown significant effects in the treatment of MET amplification in GC patients.

Crizotinib, a selective small-molecule oral inhibitor of the anaplastic lymphoma kinase (ALK), MET, and ROS proto-oncogene 1 (ROS) RTKs, is currently approved for patients with high levels of MET amplification in non-small cell lung cancer (NSCLC) (13). However, it is not approved by the Food and Drug Administration (FDA) and National Medical Products Administration (NMPA) for GC patients with MET amplification, and still in clinical trials. In a large screened cohort (n=570), 35 patients were found to be MET amplified and 9 were treated with crizotinib. Crizotinib shows encouraging results with 55.6% best overall response rate (ORR) was 55.6%, 3.2 months median progression-free survival (PFS), and 8.1 months OS in chemo-refractory MET amplification esophageal and gastric adenocarcinomas (14). Here, we report a rare case of GC patient with MET gene amplification who treated with crizotinib for three years and gained an additional high quality of life during treatment. We present this following case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-118/rc).

Case presentation

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal. For the mouse model, all procedures were performed under a project license (No. 2021-KY-0192) granted by ethics board of Henan Cancer Hospital, in compliance with institutional guidelines for the care and use of animals.

In January 2019, a 64-year-old Chinese male patient presented to our hospital with abdominal distention, then he was diagnosed as a medium to low-differentiated adenocarcinoma of the stomach (cTxN0M1) by gastroscopy. Immunohistochemistry (IHC) results of the patient’s primary tumor showed MLH1(−), MSH2(−), MSH6(−), PMS2(−), and HER2(−). Programmed cell death ligand 1 (PD-L1) combined positive score (CPS) in primary was also negative. Subsequent laparoscopic exploration revealed peritoneal seeding. Pathology of the abdominal wall nodules biopsy showed metastatic adenocarcinoma. The patient’s primary tissues were subjected to next-generation sequencing (NGS, Genecast Biotechnology, Wuxi, China), and the results showed the presence of MET amplification with a copy number (CN) of 7.54 (Table 1). Intraoperative paclitaxel 30 mg intraperitoneal infusion chemotherapy was performed. After six cycles of chemotherapy with S-1 (tegafur, gimeracil and oteracil porassium capsules, 60 mg) on days 1–14 and nab-paclitaxel (200 mg) on days 1, 8, the patient’s best outcome was evaluated as stable disease (SD), but the patient discontinued the therapy in May 2019 after significant myelosuppression and intolerable side effects such as malaise and nausea. Since there was no suitable drug to choose from, so the patient was given crizotinib therapy based on the amplified CN of MET gene (CN 7.54) on May 22, 2019.

From 22 May 2019, the patient received crizotinib at a dose rate of 250 mg twice daily. At the beginning of treatment, chest computed tomography (CT) showed a slightly thickened localized stomach wall and a cyst in the left kidney (Figure 1A,1B). After one year of crizotinib treatment, the CT results showed a slight reduction in the thickness of the stomach wall (Figure 1C,1D). The above CT results indicated that the patient’s disease was stable during treatment with crizotinib. Thirty-four months later, the examination revealed a dramatic increase in tumor markers, such as carbohydrate antigen199 (CA199), which increased to 322.4 U/mL, about 16 times of the initial diagnosis. Meanwhile, positron emission tomography-CT revealed that tumor tissue was still metabolically active in the stomach, accompanied by pleural effusion, peritoneal metastasis and other symptoms. As of March 2022, the patient treated with crizotinib had a PFS of 34 months.

Figure 1 Chest computed tomography during crizotinib treatment from 2020 to 2022. The patient’s gastric cancer disease was evaluated as SD during the administration. FOV, field of view; SD, stable disease.

After disease progression (PD) occurred, due to lack of suitable treatments, the gastric tumor tissue was sequenced for a second time by target-capture sequencing of 1021-gene panel (Geneplus-Beijing Institute, Beijing, China). The sequencing results showed that MET amplification was no longer detected after crizotinib treatment. Other mutations, such as kirsten rat sarcoma viral oncogene homologue (KRAS), tumor protein p53 (TP53) mutations, caspase recruitment domain family member 11 (CARD11), lysine methyltransferase 2D (MLL2), kinetochore localized astrin binding protein (C15orf23), remained as before (Table 2). In addition, the immunohistochemical distribution of PD-L1 protein in the stomach showed negative results [combined positive score (CPS): 1, tumor proportion score (TPS) <1%]. Based on the above results, immunotherapy was not considered at present. In order to find an effective treatment for this patient, we constructed a mini patient-derived xenograft (miniPDX) mouse model for targeted drug screening, and the experimental protocol is shown in Table 3. We selected adavosertib plus olaparib based on TP53 p.F270C (15), and Trametinib based on KRAS amplification (16) with secondary drug resistance mutations. In addition, we are still testing whether the patient can benefit from crizotinib, as well as other chemotherapy treatments. The entire time from the onset of PD in the patient to the availability of drug susceptibility results in the miniPDX model took about 2 weeks. Based on the relative value-added results, the trametinib group had the best performance, with values below 50%, while the adavosertib plus olaparib group and crizotinib group showed only lower results than the trametinib group (Figure 2A). The changes in body weight during the administration of trametinib in mice also showed that trametinib treatment had a small effect on body weight and did not fluctuate much during the administration of the drug (Figure 2B). From April 22, 2022 to October 12, 2022, the patient has been treated with 2 mg trametinib monotherapy once a day, and had benefited with the efficacy evaluation of SD with a dramatic decrease in CA199 tumor markers. From April 22, 2022 to June 29, 2022, CA199 decreased from 322.4 to 182.4 U/mL, unfortunately with severe side effects, such as bloating, poor appetite, fatigue and constipation. After October, the patient went to another hospital for treatment, and was lost to follow-up. In summary, the GC patient with MET amplification acquired three years of PFS with crizotinib therapy. Subsequently, the patient benefited from trametinib screened from miniPDX mouse model for at least a few months.

Figure 2 PD-L1 protein expression distribution in gastric tissue and drug efficacy miniPDX mouse model. (A) Relative value-added rate of drug-treated tumor cells; (B) changes in body weight during drug administration in mice. The relative proliferation rate of tumor cells (T/C% = T/C × 100%. T and C are the cell viability values of the administered and control groups, respectively), i.e., the percentage value of relative proliferation in the administered and control groups. The lower the value, the higher the inhibition rate of the drug/combination on the tumor-bearing cells. Ola, olaparib; Ada, adavosertib; 5-FU, 5-fluorouracil; CF, calcium folinate; Oxa, oxaliplatin; Irino, irinotecan; Nab-pac, nab-paclitaxel; Apa, apatinib; RCBW, rate of change in body weight; PD-L1, programmed cell death ligand 1; miniPDX, mini patient-derived xenograft.

Discussion

As one of the leading contributors to global malignancies incidence and mortality worldwide, GC is usually diagnosed in advanced stages, and it often presents a poor prognosis (17). Overexpression of MET occurs frequently in GC and has been proposed as a potential predictive biomarker for targeted therapy (18).

Crizotinib is a small molecule inhibitor of anti-MET approved by the FDA for lung cancer treatment (19). However, it is not been approved by the FDA for GC patients with MET amplification. The French-crizotinib trial (NCT02034981) demonstrated that crizotinib showed encouraging results in MET-amplified GC patients (14). Therefore, crizotinib was recommended based on the high CN of MET gene, and the patient achieved a prolonged remission. Three years later, the patient developed resistance and tumor progression.

By this time, NGS results revealed MET amplification mutation no was longer detected after crizotinib administration in this GC patient, while KRAS amplification and TP53 gene mutations remained. KRAS amplification may indicate tumor progression, and the constitutive activation of RAS-RAF-MEK-ERK signaling pathway, which will promote tumor growth and proliferation. Data suggest that inhibitors of mitogen-activated protein kinase 1 (MEK1) and mitogen-activated protein kinase 2 (MEK2), which inhibit the KRAS downstream signaling pathway, may be a good choice for KRAS mutant as a therapeutic tool (20). Trametinib, a MEK1/2 inhibitor, inhibits cell proliferation by affecting the MAPK pathway, primarily through its action on MEK protein, a downstream signaling protein of RAS and Raf-1 proto-oncogene (RAF), so trametinib may also be effective against cancer types with RAS or RAF mutations (21). Although trametinib has been shown in most studies to work by inhibiting KRAS in lung cancer treatment, it is rarely reported that GC can benefit from trametinib.

As cancer development becomes more and more complex, the degree of control of the disease process by conventional drugs becomes increasingly unacceptable and even harmful to patients. As a result, customized treatments are becoming increasingly important. With the popularity of genetic testing, customized screening protocols are becoming more accessible, and even patient-derived tumour xenografts (PDTX) samples can be as accurate as 90% for drug efficacy and resistance rates (22-24). Based on the results of this case, trametinib did show good anti-GC effects, even though trametinib is not traditionally the best drug for treating GC.

This study reports a GC patient with MET amplification received crizotinib and obtained the PFS of 34 months. After three years of crizotinib treatment, the patient developed resistance and tumor progression. NGS showed that MET amplification disappeared, which is rare in patients with GC. Because the patient refused chemotherapy, miniPDX mouse model was performed after progression to screen suitable drugs, and finally the patient was given trametinib treatment according to drug sensitivity. The tumor marker CA199 decreased significantly over two months of trametinib monotherapy, and CT results on June 30, 2022, showed stable disease (data not shown). The case report showed that the patient benefited from crizotinib and trametinib respectively after first-line chemotherapy and provided a reference for the use of genetic testing to identify mutation sites and select treatment options.

Conclusions

In the case, the potential drug target of GC was identified through genetic testing and treated with crizotinib firstly. After drug resistance developed, NGS was reapplied again to identify some new mutation sites. Finally, the drug was used experimentally across indications and treated with trametinib from April 22, 2022 to October 12, 2022. This shows that genetic testing is becoming more widely accepted in cancer treatment today.

Acknowledgments

Funding: This work was supported by the Medical Science and Technique Foundation of Henan Province (No. LHGJ20200185 to W.X.), and Science and Technique Foundation of Henan Province (No. 212102310771 to W.X.).

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-118/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-118/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-118/coif). Z.L. and H.K. are employees of Geneplus-Beijing (Beijing, China). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal. For the mouse model, all procedures were performed under a project license (No. 2021-KY-0192) granted by ethics board of Henan Cancer Hospital, in compliance with institutional guidelines for the care and use of animals.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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