A Special Interview with Elsevier 2021 "Highly Cited Chinese Researcher": Professor Jia Fan

The Associate Editor of Hepatoma Research, Professor Jia Fan was recently named to the list of Elsevier 2021 "Highly Cited Chinese Researchers". The Editorial Office of Hepatoma Research invited Prof. Jia Fan, an Academician of the Chinese Academy of Sciences and president of Zhongshan Hospital affiliated to Fudan University, for this exclusive interview. As the interviewer, Prof. Guangwen Cao, the Editor-in-Chief of Hepatoma Research and Chairman of the Department of Epidemiology from Second Military Medical University, had in-depth communication with Prof. Jia Fan.

Professor Jia Fan

• Academician of Chinese Academy of Sciences
• President of Zhongshan Hospital affiliated to Fudan University
• Chairman of the Shanghai Institute of Liver Diseases; Director of the Shanghai Clinical Research Center for Liver Cancer
• Director of the Liver Cancer Institute, Fudan University; Director of the Department of Oncology and Organ Transplantation Center, Zhongshan Hospital, Fudan University; Director of the Fudan Zhongshan Cancer Center
• Chairman of the Expert Committee on Quality Control of Liver Cancers, National Cancer Center
• Association President of Chinese College of Surgeons
• President of the Chinese Society of Liver Surgeons (CSLS)
• Vice Chairman of CSCO; executive director of the Chinese Medical Association; Fellow of the American College of Surgeons (FACS); Member of the American Society of Clinical Oncology (ASCO); Member of the American Society of Surgical Oncology (SSO)
• Chairman of the Compilation Expert Committee on Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2017 Edition, 2019 Edition), Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition)

Prof. Fan has been devoted to clinical diagnosis and treatment as well as basic research of hepatic cancer surgery for more than three decades. He also proposed suitability guidelines for liver transplantation in China, known as the “Shanghai-Fudan criteria”. To date, he has published more than 575 papers in SCI journals, with 182 of them as the first or the corresponding author in journals such as Cell (2 papers), Nature, Lancet Oncology, Cancer Discovery, Cancer Cell, Journal of Clinical Oncology, Gastroenterology, Hepatology, and Gut. One of his papers has been cited 1105 times. As the first author, he was awarded the first prize in the State Natural Science Awards(2016) and the second prize in the State Science and Technology Advancement Awards (2012 and 2008); as a key participant, he was awarded the second prize in the State Science and Technology Advancement Awards twice (2015 and 2020) and the first prize in the State Science and Technology Advancement Awards(2006). In recent years, he has undertaken more than 30 national, provincial, and ministerial projects, such as the National Science and Technology Support Program. He was bestowed with the Tan Jiazhen Life Science Innovation Award (2016), Scientific and Technological Progress Prize from the Ho Leung Ho Lee Foundation (2016), Wu Jieping-Paul Janssen Medical & Pharmaceutical Award (Wu-Janssen Award) (2016), Chinese Physician Award (2016), Top Ten Outstanding Scientific and Technological Workers in China (2012), Top Ten Health Guardians in China (2012), Model Worker of Shanghai (2010), National Model Worker (2010), and Fok Ying-Tung Prize-Globally Outstanding Chinese Doctor Award (2020) among many others.

Q & A

Q1：We know that since last year, you’ve been taking the lead in hosting the China Summit Forum for Liver Cancer Conversion Therapy. Just recently on May 15th, you finished the 8th sub-forum. Which potential groups do you think are suitable for conversion therapy? How do you determine a personalized conversion therapy regimen? For the development of conversion therapy in hepatocellular carcinoma (HCC) patients, what objectives can we take into consideration for further studies in the future?

Jia Fan: The new edition of Guidelines for the Diagnosis and Treatment of Primary Liver Cancercontains unprecedented breakthroughs in the understanding and treatment of HCC. In the past, some operable patients with HCC were treated surgically while those patients who could not be operated on were able to choose radio frequency (RF) and systemic therapy. In those days, about 20% of HCC patients could go for surgical treatment, but now it’s about 30%. We all know that surgical treatment is the best curative option for HCC patients. So, in recent years, research on conversion therapy of HCC has attracted more and more attention. We also mentioned conversion therapy in Guidelines for the Diagnosis and Treatment of Primary Liver Cancer, which contains more new methods, drugs and means of conversion therapy than guidelines from the past five or even ten years. If we can enable 20-30% of HCC patients to meet the criteria for surgical treatment through these new methods and means, then 50-60% of HCC patients can receive surgical treatment. Regardless of the tumor size or treatment post-conversion surgery, the overall 5-year survival rate of patients now reaches 65%. That’s really high. Nonetheless, the overall 5-year survival rate of HCC in China is only about 14%. If 50-60% of Chinese patients with HCC can have surgical resection, their 5-year survival rate will be significantly improved. We have studied and analyzed nearly 20,000 surgeries in patients with smaller tumors. If the original large tumor is transformed into a small one, the 5-year survival rate of surgical treatment can reach over 70%. For surgeries with liver tumors less than 3cmin size, the 5-year survival rate can reach more than 80%. This is the curative effect expected from conversion therapy. Today’s conversion means, methods and ideas are completely different from those in previous years. The first is two-stage hepatectomy-Associating Liver Partition and Portal vein Ligation for Staged hepatectomy (ALPPS). For example, a large tumor in the right liver extends to the left, but the left outer lobe of the left liver is very small, and the remaining liver volume does not reach 0.8% or even 0.6% of a patient’s body weight. In this case, although the liver function is normal before surgery, the surgery will lead to post-hepatectomy liver failure. So if the tumor cannot be removed in one surgery, it is necessary to separate the normal part of the liver from the cancerous section. After the separation, the right branch of the portal vein (PV) supplying the right side is directly ligated. However, the tumor will not be removed because removing the liver is not tolerable. It will take about 7-10 days for the volume of the left liver to double in size. Perhaps it is originally only 0.4-0.5% of body weight; after doubling, this volume will reach more than 0.8% or even 1%. It will then be safer to have the tumor removed in a second operation. We call this the ALPPS procedure. This operation is frequently performed all over the world, and the conversion rate is quite high. Generally speaking, the average survival time of patients with a large liver tumor that cannot be removed in one surgery is about half a year. However, after the ALPPS procedure, the 5-year survival rate of patients can reach 50-60%. The second is interventional therapy with a conversion rate of about 15%. This type of conversion should take into consideration liver developments, such as severe hepatic cirrhosis and inflammation of the liver. If intervention is done, the probability of tumor reduction or necessity for a two-stage hepatectomy is relatively low. The third is HAIC (hepatic arterial infusion chemotherapy), which is a type of continuous perfusion chemotherapy through the hepatic artery. For quite a lot of patients with HCC, after HAIC, their original large tumors or multiple tumors can be reduced and subsequently removed as small tumors. Most HAIC uses FOLFOX, so some patients can successfully meet the criteria for surgical treatment after conversion therapy. The fourth is systemic therapy. With the emergence of immunotherapy in recent years, there are targeted drug therapies using small molecules, immunotherapy, antibody therapy for tumor angiogenesis, including TKI, targeted PD-1therapy, PD-L1 antibody drugs, VEGFR inhibitors, bevacizumab therapy and combined approaches among others., For instance, targeted therapy and immunotherapy are considered to be such acombination. This combination means that targeted drugs like lenvatinib mesilate can be combined with immunotherapies like PD-1 and PD-L1 antibodies; there are many targeted drugs and immunotherapies coming from both domestic and imported sources. Through combined treatment, the original large tumor in about 15-20% of patients can be converted into small tumors that are subsequently removed with surgical resection. In addition, there is Roche’s therapeutic combinationusing IMbrave 150, and sintilimab injection with bevacizumab analogues by the Chinese company Innovent, which are named Byvasda and Tyvyt. Evaluating the combination of these two drugs is the objective of a registered clinical study initiated by myself, and the results have been published in The Lancet Oncology. Roche’s IMbrave 150 (not yet payable with medical insurance) is an immunotherapy PD-L1 monoclonal antibody combined with bevacizumab, an anti-vascular endothelial growth factor (anti-VEGF) antibody. In addition, there are anti-CTLA-4 monoclonal antibodies, cytotoxic T lymphocytes with PD-1 and further targeted treatments with other combined therapies. All these treatments, such as targeted therapy-based combinations, immunotherapy, angiogenesis inhibitors and cytotoxic cells are combined therapies for different targets, which are also approaches for conversion therapy. There are other combinations, such as intervention with immunotherapy, intervention with targeted therapy and intervention with a combination of immunotherapy and targeted therapy. The fifth is radiation therapy (also called radiotherapy). Radiotherapy can also lead to regression for a large number of tumors in patients, especially for deep tumors close to large blood vessels. These treatments should also be combined with other systemic treatments to promote tumor shrinkage. These are the methods and philosophies of our conversion therapy. So it’s not so serious as we think it is for an inoperable patient. Originally, those large tumors were only suitable for systemic treatment but a radical cure was difficult to achieve. However, it is also possible that after these systemic treatments, some small tumors can be removed, or even tumors in stage IIIa or IIIb can be converted into IIa or IIb. Subsequently, other treatments can be performed. This procedure is sequential. These are the approaches that we use to promote conversion therapy. Of course, there are other combinations with traditional Chinese medicine (TCM), and some TCM are propulsives and adjuvants. In a nutshell, current treatments are more diverse than before, and we are always on the lookoutto study and explore more methods for treating HCC.

Q2: The new achievement in the research paper by you and your team, Proteogenomic Characterization and Clinical Staging of Intrahepatic Cholangiocarcinoma (ICC) was a systematic drawing of the multidimensional molecular map of ICC for the first time. This provides a new perspective for the pathogenesis and development mechanism, scientific molecular typing, prognosis judgment and personalized treatment strategy of ICC. For this type of multi-omics analysis strategy with proteomics at the core, what is its significance and implication for further research on the development and treatment of ICC in the future?

Jia Fan: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary malignancy in the liver. It is characterized by a challenging diagnosis at an early stage, low surgical resection rate, high malignancy, vulnerability towards the involvement of peripheral organs and distant metastasis, insensitivity to radiotherapy and chemotherapy as well as poor prognosis. The 5-year survival rate after surgery is only 20-30%and there are no effective targeted therapies or immunotherapies. Therefore, it is particularly necessary to clarify the pathogenesis of ICC and make more accurate gene and molecular mappings so as to provide atheoretical basis for identifying new diagnosis and treatment targets and realizing personalized treatment. This study comprehensively analyzed the panorama of ICC molecular characteristics while providing new perspectives and strategies for clinical diagnosis and treatment of ICC. We utilized samples from 262 patients with ICC who underwent liver resection surgery in Zhongshan Hospital. Then, we systematically drew a multi-dimensional molecular map of ICC for the first time based on multi-dimensional and multi-omics (genomics, transcriptomics, proteomics, phosphoproteomics and microbiomics) data. The map provides a new perspective for the pathogenesis and development mechanism, scientific molecular typing, prognosis judgment and personalized treatment strategy of ICC. In this study, we established the molecular typing of ICC patients with proteomics at the core: inflammatory type (S1), interstitial type (S2), metabolic type (S3) and differentiated type (S4). These four subtypes have their own characteristic genome, immune microenvironment, treatment strategies and clinical prognosis. As such, they are of great significance in determining clinically personalized diagnosis and treatment. In this study, we’ve also specified the targeted potential therapeutic targets of five main driving genes (TP53, KRAS, FGFR2, IDH1/2, BAP1) of ICC. The relationships between these mutations and biological processes such as cell cycle, drug metabolism and inflammation-infection are also revealed. In addition, the study indicated that the gene mutation fingerprints caused by aflatoxin (AFT) and aristolochic acids (ACs) played an important role in the pathogenesis and development of ICC, which provided clues for etiological prevention. In particular, it was found that 10% of ICC has fusion and mutation of the FGFR2 gene. The FGFR2 fusion protein not only drives the pathogenesis and development of ICC, but also produces new targeted therapeutic targets. Furthermore, antigenic peptides derived from several fusion proteins have strong immunogenicity and can enable the activation and expansion of specific T cell populations. These are therefore also potential immunotherapy targets. Through the integration of multi-omics data, this study revealed the molecular characterization, pathogenesis and development mechanism of ICC. It is a result of effective cooperation between clinical science and proteomics, and it is a breakthrough in diagnostic markers and therapeutic targets of major diseases. These achievements will further expand China’s advantages in the field of precision medicine, promote the innovative development of the bio-pharmaceutical industry and make great contributions toward exploring tumor heterogeneity and realizing personalized treatment.

Q3：The National Health Commission of China has released the Guidelines for the Diagnosis and Treatment of Primary Liver Cancer(2022 Edition). We know that you are one of the key drafters. Can you talk about the developments of liver cancer treatment in 2021? What innovations or contribution does China make in these Guidelines?

Jia Fan: There are ten academicians involved in compiling Guidelines for the Diagnosis and Treatment of Primary Liver Cancer(2022 Edition)and about one hundred experts in various fields of liver cancer, including diagnostics, epidemiology, statistics, clinical therapy, psychology and palliative therapy (care). We have many compilation groups, such as a surgical group, internal medicine group, interventional therapy group, diagnosis group, pathology group and systemic therapy group. So, this is a collaborative effort by Chinese experts. In addition, the China Clinical Practice Guideline Alliance (GUIDANCE), founded by Academician Han Qide and Professor Wang Jiyao, mainly studies evidence-based medicine (EBM), which is divided into high-level, medium-level and low-level segments. They are equivalent to levels I/II/III in the previous EBM, with Ia and Ib also being covered. At present, China has formulated many guidelines, but it’s very challenging for many of them to be recognized internationally. The main reason is that the level of evidence-based medicine we adopt is not high enough. We do not have sufficient prospective and multi-center randomized controlled trials (RCT) in our clinical study. In terms of the diagnosis and staging of liver cancer, there are many international guidelines, such as the BCLC staging, TNM staging, JSH staging in Japan and APASL (Asian-Pacific Association for the Study of the Liver) staging, but they are not suitable for liver cancer in China. Our guidelines are somewhat different from theirs, because the characteristics of the etiology and development of liver cancer in China are different, including some underlying diseases. Our staging is called CNLC, which is divided into stages Ia, Ib, IIa, IIb, IIIa, IIIb and IV. The appropriate treatment can only be selected usingclearly defined stages. This staging approach that takes into account China’s national conditions broadens the range of conditions for which surgeries and transplants can be applied to. In addition, multi-modal therapy is encouraged. In contrast, the international guidelines prefer the principle of “one stage, one therapy”. This consequently leads to a lower possibility of conversion therapy. One of the advances made in the Guidelines for the Diagnosis and Treatment of Primary Liver Cancer(2022 Edition) is combination therapy. Now, there are many new drugs that are based on a combination of targeted therapy and immunotherapy. In addition, this method of combined therapy is different from the past. It used to be targeted therapy, immunotherapy, or targeted therapy combined with immunotherapy. Now, it’s targeted therapy combined with immunotherapy or immunotherapy combined with angiogenesis inhibitors, possibly even combined with chemotherapy, interventional therapy, radiotherapy and radiofrequency ablation, etc. Finally, the Guidelines presents advances in the treatment of liver cancer to prevent recurrence and metastasis. For original recurrent and metastatic liver cancer, such as tumors larger than 5cm, multiple tumors, or tumors with microvascular invasion, we choose interventional therapy to prevent its recurrence and metastasis after surgical treatment. Now, there are new potential regimens. After surgical resection, be it a large or small tumor, we can choose a combination of targeted therapy with immunotherapy, intervention with targeted therapy and immunotherapyor intervention with targeted therapy. It is expected that these studies will result in better therapeutic effects.

Q4：What do you think about the prospect of immunotherapy being combined with the latest targets for advanced liver cancer?

Jia Fan: Targeted therapy for advanced HCC emerged more than ten years ago, such as with sorafenib, one of the typical TKIs. It has been used for the treatment of HCC since 2008, and regorafenib appeared afterward. Now, the most representative drug is lenvatinib. Compared with sorafenib, lenvatinib has the same or even better therapeutic effects. Immunotherapy has only sprung up in the past three years, and several immune checkpoint inhibitors (ICI), such as PD-1, PD-L1 and CTLA-4have been detected as the targets. For immunotherapy, if we use anti-PD-1, PD-L1 or CTLA-4 in the treatment, the response rate is about 15-25%. The response rate of targeted therapy is about 5-10%, but its mechanism of action is different. The combination of immonotherapy and target therapy These two therapies can have a synergistic effecworks better than a single therapy of these two. As of now, for immunotherapy and targeted therapy, we can choose either one or both. In my opinion, combined therapy is better, but it has some side effects. Determining which therapy to use should be based on the patient’s tolerance to the drug and its side effects. The therapeutic effect of combining immunotherapy with targeted therapy is absolutely better than that of one single option, so I think that in the future, we can develop more innovative drugs with fewer side effects and better therapeutic effects. It’s the same for immunotherapy. There are many drugs in immunotherapy such as drug O, but each has its side effects. Therefore, I think targeted therapy combined with immunotherapy will be a promising systemic treatment in the future.

Q5：What are your research interests this year or over next few years? Would you mind sharing it with us?

Jia Fan: As far as fundamental research is concerned, we are interested in immune microenvironments, immune microecology, focusing on the tumor cells themselves and the influence of interstitial cells in immune environments on pathogenesis and development of a tumor. And we’ve also delved into the omics. Second, we will conduct in-depth research regarding omics. Apart from staging, we can detect some targets for future conversion therapy. The early diagnosis of liver cancer, including circulating tumor cells (CTCs), is also one of our present research priorities. In terms of clinical research, we have our own projects, as well as collaborative projects with pharmaceutical enterprises, in which we make joint effects in phase I/II/III clinical trials. In addition, we are also doing research on anti-recurrence and metastasis of liver cancer. Finally, we are still doing some translational research, including research and development of drugs. Currently, we have attained some achievements. We hope that new drugs can be developed and find clinical applications, and that there will be some new breakthroughs in treatment.