Editor-in-Chief, Professor Xiong Jianping
In the clinical real world for physicians the most enlightening significance is case sharing, in the face of ever-changing patients if you can grasp the core of clinical diagnosis and treatment, then the ever-changing, whether the patient to obtain a good long-term survival, often in a key choice of physicians, so as an oncology clinician to continue to learn the latest knowledge, constantly summarize clinical experience, carefully analyze the changes in the condition is extremely important. The number of beds in our digestive tumor team has reached 200, and 1500 people are treated for digestive tumors every year, which has worked hard to relieve the pain of digestive tumor patients in our province and has been widely praised. In this issue of case sharing, young physicians invariably choose the successful cases that are impressive in their own medical practice process and bring better curative effects to patients, we see that starting from mastering the basic knowledge, reasoning clinical practice and application, when the multi-line treatment of the disease is still progressing and endangering the patient's life, as far as possible according to the guidance of precision medicine, choose the latest immunotherapy or targeted therapy, so that the patient's peak circuit turns to willow dark flowers and bright to regain a new life.
Executive Editor of this issue
Professor Jianping Xiong
Chief Physician, Second-level Professor and Doctoral Supervisor of the Department of Oncology, The First Affiliated Hospital of Nanchang University
Jiangxi Provincial Government Special Allowance receives experts
Member of the Oncology Branch of the Chinese Medical Association
Member of the Standing Committee of the Clinical Oncology Branch of the Chinese Association of Women Physicians
Standing Committee Member of the Supporting Treatment Professional Committee of the Chinese Anti-Cancer Association / Standing Committee Member of the Chemotherapy Professional Committee / Standing Committee Member of the Lung Cancer Special Committee
Director of the Chinese Oncology Clinical Society
Phase II
Professor Xiong Jianping strongly recommends: "A case report of a hepatocellular carcinoma patient with both dMMR and EGFR "sensitive" mutations who did not respond to EGFR-TKI treatment"
The authors of this article: Huang Shanshan, Li Jun, Xiang Xiaojun, Xiong Jianping, the First Affiliated Hospital of Nanchang University
Junhe Li associate professor
Deputy Chief Physician, Associate Professor and Doctoral Supervisor of the Cancer Medical Center of the First Affiliated Hospital of Nanchang University
Member of the Cancer Palliative and Rehabilitation Professional Committee of the Chinese Anti-Cancer Association
Member of CMUP Professional Committee of Chinese Anti-Cancer Association
Huang Shanshan
Physician, attending physician and doctor of the Department of Oncology of the First Affiliated Hospital of Nanchang University
He published 6 SCI papers as the first author, accumulating 20 if >
He presided over 1 natural science foundation of Jiangxi Province and 1 fund of the Provincial Health Commission
Returnee, Visiting Scholar, Singapore Science and Technology Research Council (A*STAR).
The text is as follows
summary
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are approved worldwide for the treatment of patients with advanced non-small cell lung cancer (NSCLC) with EGFR mutation-positive. However, there have been few reports of the use of EGFR TKIs for the treatment of mutation-positive malignancies other than NSCLC. Here, we report a patient with primary hepatocellular carcinoma (HCC) who has a combination of a mismatch repair protein deletion (dMMR) and an exon EGFR 19 deletion, who received the first-generation EGFR-TKI (gefitinib) therapy. However, after 1 month of treatment with gefitinib, the patient's condition deteriorated. Since then, he has received treatment with immune checkpoint inhibitors and obtained good treatment results. To date, the patient has not observed any signs of disease progression in the past 21 months. This case shows that EGFR is not a driver gene for HCC and that EGFR TKI is not effective in patients with HCC with EGFR "sensitive" mutations.
preface
Liver cancer is one of the most common digestive malignancies and the third leading cause of cancer-related deaths worldwide [1]. China has more than 373,000 new cases each year, accounting for nearly half of the global incidence [2]. Liver cancer mainly includes two histological subtypes: hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC)[3]. In general, 70%-75% of liver cancers are HCC. Key risk factors for HCC include chronic hepatitis B (HBV) and hepatitis C virus (HCV) infection, cirrhosis, and excessive alcohol consumption [4]. Due to the lack of specific symptoms, most patients with HCC are diagnosed at an advanced stage and lose the opportunity to undergo radical hepatic resection [5]. Therefore, palliative systemic therapy has important implications for patients with advanced HCC.
Currently, sorafenib, rigofenib, and renvatinib have been approved for first- or second-line treatment of advanced HCC [6]. Due to limited treatment options, the overall survival benefit in patients with advanced HCC is rather limited. Recently, immunotherapy has shown therapeutic potential in a variety of malignancies [7-9].
The epidermal growth factor receptor (EGFR) is one of the most commonly altered oncogenes in solid carcinoma [10]. EGFR kinase activation mutations and overexpression of the EGFR protein are the two main ways in which the EGFR gene is altered in tumors [11], and these changes can lead to abnormal activation of EGFR signaling. Abnormal activation of EGFR and its downstream genes promotes a number of biological processes, including cell proliferation, migration, and angiogenesis [12]. At present, some measures have been developed to target abnormal changes in EGFR in tumor patients, such as tyrosine kinase inhibitors (TKIs). EGFR TKIs have been recommended as first-line therapy in patients with advanced NSCLC with positive EGFR mutations. However, there have been few reports of the use of EGFR TKIs for the treatment of mutation-positive malignancies other than NSCLC. We report here a primary hepatocellular carcinoma with an exon deletion mutation in EGFR 19 and received treatment with the first generation of EGFR-TKI (gefitinib).
Case introduction
A 53-year-old male with a previous history of chronic hepatitis B infection > 20 years. 2019-10-07The results of chest CT scan during physical examination suggest that lung metastatic tumors may be possible. In order to confirm the diagnosis, on 2019-10-10, the results of ct of the whole abdomen of the chest and abdomen (flat scan + enhancement) were performed in the outpatient clinic of our hospital: 1. The right lobe of the liver is a mass, considering primary liver CA, and multiple lymph node metastasis in the retroperitoneum; 2. Cirrhosis, splenomegaly. 3. Multiple nodules in both lungs, consider metastases (Figure 1).
2019-10-22Pathological results of left lung puncture in our hospital: (left lung puncture) low-differentiation carcinoma, first consider metastatic carcinoma, immunohistochemical results are as follows: CK7 (3+); CK20(-); Villin(3+); Hep(-); Galectin-3(3+); CK19(2+); TTF-1(-); NapsinA(-); P40(-); P63(-); Ki-67(30%+); HSP70(+); Gly(-); CD56(-); Syn (weak +); CgA(-); P504S(-); PSA(-)。 Based on the above findings, the patient was diagnosed with stage IV HCC with lung metastases and retroperitoneal lymph node metastases. In addition, the patient underwent a second-generation sequencing (NGS) test that showed that the patient had an "sensitive" mutation in EGFR, p.E746_A750del in exon 19 (VAF: 16.36%). We also performed immunohistochemization of four mismatch repair proteins to the patients' lung punctures, and the results showed MLH1(-), PMS2(-), MSH2(+), MSH6(+). How to choose the patient's first-line treatment plan? EGFR TKI or immune checkpoint inhibitor?
Based on some previous experiences in NSCLC, patients with EGFR mutant lung cancer respond poorly to immune checkpoint inhibitor therapy [13-15]. Some patients with EGFR mutations even show tumor hyper-progression after receiving immunotherapy [16,17]. Therefore, we first recommend patients oral gefitinib (250 mg, qd). However, after 1 month of treatment, CT of the patient's chest and abdomen shows liver masses as well as enlargement of retroperitoneal lymph nodes and lung metastases (Figure 2).
At the time, the first-line drug approved for HCC was sorafenib, renvatinib, or systemic chemotherapy. Immune checkpoint inhibitors are only recommended as second-line agents in the 2019 NCCN guidelines. However, we take into account the patient's mismatch repair protein expression deficit, which suggests that patients may have a good response if they receive immunotherapy. So we subsequently decided to use immunotherapy (carrelizumab 200 mg D1/q3w) as the treatment plan for this patient. Surprisingly, after two cycles of treatment, CT scans showed significant reductions in liver masses, retroperitoneal lymph nodes, and lung metastases compared to baseline (figure 2). To date, the patient's overall survival time has exceeded 21 months.
discuss
In NSCLC, dysregulation of tyrosine kinase activity of EGFR can lead to increased proliferation, invasion, and metastasis of malignant cells. Treatment with EGFR-TKIs can produce significant antitumor activity in patients with NSCLC with EGFR mutations [18,19]. The most common sensitizing mutations are EGFR 19 exon deletion mutations and exon 21 L858R point mutations, which account for 90 percent of EGFR mutation types [20]. Although EGFR has the highest mutation rate in lung cancer [21], EGFR mutations are also present in other malignancies, such as conventional glioblastoma, glioblastoma, colon cancer, and so on (Figure 3).
Phase II clinical studies have shown that gefitinib or erlotinib has an overall objective response rate of 8.8 percent in patients with esophageal cancer [22-23]. In another Phase II clinical study, 80 patients with gastric cancer showed no response to treatment for EGFR TKI [24,25]. We can't help but wonder if EGFR TKI is effective for hepatocellular carcinomas that carry EGFR "sensitive" mutations?
Immunotherapy has changed the treatment of many advanced cancers. However, immunotherapy has not yielded any benefit in patients with NSCLC with EGFR mutations and ALK rearrangements [26,27]. CheckMate 012[28] is a Phase I study evaluating the efficacy of nivolumab monotherapy/combination regimen as a first-line treatment for advanced NSCLC. Compared with the EGFR wild-type group, a lower response rate and a lower survival benefit were shown in the EGFR mutation subgroup of the monotherapy cohort. (ORRs were 14% and 30%, respectively; median PFS, 1.8 and 6.6 months, respectively). In addition, in a Phase II study, the study investigated the efficacy of pembrolizumab in patients with EGFR mutations who had not received TKI treatment, PD-L1-positive advanced NSCLC. Tumor retraction was not observed in any of the 11 enrolled patients [29]. In addition, the researchers suggest that EGFR mutations may serve as a predictor of tumor hyper-progression in patients receiving immunotherapy in advanced NSCLC [16]. Therefore, we first recommend that patients take 250 mg of gefitinib per day for first-line targeted therapy. However, the patient developed disease progression after taking gefitinib for 1 month.
EGFR mutations are detectable in approximately 15 percent of lung adenocarcinomas in Western countries, and are higher in Asian, female, and patients who have never smoked or who have smoked mildly [30,31]. However, in HCC, data on EGFR mutations are limited. Two previous studies reported that no EGFR mutation was detected in HCC [32,33]. However, with the advent of more sensitive sequencing techniques, subsequent studies reported detecting EGFR mutations in HCC tissues at 13/33 (39.4%) and 11/33 (33.3%), respectively [34]. Notably, most of the reported mutations are rare, and no significant association between EGFR mutations and EGFR overexpression, Ki-67, tumor size, and other clinical parameters was detected. Therefore, we speculate that EGFR is not the driver gene for HCC, which may explain why this patient does not respond well to gefitinib treatment. Of course, large sample studies are needed to validate our assumptions.
High sensitivity to immunotherapy in patients with tumors due to the loss of mismatch repair proteins [35]. Thereafter, we decided to use immunotherapy (carreizumab 200 mg D1/q3w) as a follow-up treatment for patients. After just two courses of treatment, we observed tumor regression in liver lesions and lung metastases. From the initial use of carellizumab to the present, patients have stable tumor control and have received regular immunotherapy for 21 months.
Li Junhe and Xiong Jianping commented
(1) The patient was a primary liver cancer (HCC) with MSI-H and exon EGFR 19 deletions, resistant to gefitinib therapy, and sensitive to PD-1 inhibitors. Although 60-85% of HCC have EGFR overexpression, but the incidence of EGFR mutations is low, Su et al. used direct sequencing methods to detect 89 HCC patients EGFR 18-21 exon mutations, none of which detected mutations that may lead to amino acid alteration/deletion; in addition, EGFR mutations in HCC may not be as driver gene mutations as in lung adenocarcinoma, Sueangoen found that EGFR mutations in HCC patients did not lead to sustained tyrosine kinase activation. Kinase activity is still partially dependent on extracellular EGF, and in vitro tests it was found that EGFR-mutated HCC cells are resistant to erlotinib, and even high concentrations of erlotinib can only partially inhibit or cannot inhibit EGFR and AKT, ERK phosphorylation, and apoptosis and autophagy, which can partially explain that although the patient carries EGFR19 exon mutation, it is not effective for gefitinib treatment.
(2) The MSI-H ratio in HCC patients was significantly lower than that of colorectal cancer, and one study continuously detected 82 cases of HCC tissue, and only 2 cases were MSI-H patients. Recent studies have found that MSI-H gastrointestinal tumors are more likely to coexist with other genetic changes such as BRAF, EGFR, type II TGF-β mutations, such as Gokare, etc. found that 45% of MSI-H colorectal cancer patients have mutations in the EGFR receptor kinase region (RTK). The patient responded well to PD-1 inhibitors, once again validating the value of MSI-H as a biomarker predicted for the efficacy of PD-1 inhibitors, and at present, based on the results of Imbrave-150, Orient-032 and KEYNOTE-524 studies, the evidence-based medical evidence of the value of immune-targeted combinations in the first-line treatment of HCC is getting stronger and stronger, and the patient's use of immune-targeted combination therapy strategies is also worth trying.
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To be continued
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