key: cord-0983695-wdp68onm
authors: Feng, Mei; Pan, Yisheng; Kong, Ruirui; Shu, Shaokun
title: Therapy of primary liver cancer
date: 2020-08-10
journal: Innovation
DOI: 10.1016/j.xinn.2020.100032
sha: 9d2aa0dc546394ccef03221135b6c1569f93a274
doc_id: 983695
cord_uid: wdp68onm

Abstract Primary liver cancer (PLC) is a fatal disease that affects millions of lives worldwide. PLC is the leading cause of cancer-related deaths and the rate of incidence is predicted to rise in the coming decades. PLC can be categorized into three major histological subtypes: hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined HCC-ICC (cHCC-ICC). These subtypes are distinct with respect to epidemiology, clinicopathological features, genetic alterations, and clinical managements, which are thoroughly summarized in this review. The state of treatment strategies for each subtype, including the currently approved drugs and the potential novel therapies, are also discussed.

• HCC HCC represents the major histologic subtype, accounting for approximately 80% of all cases of primary liver cancer. The risk factors for HCC includes hepatitis B/C viral infection (HBV and HCV), aflatoxin B1, alcoholic abuse, and non-alcoholic, metabolic symptoms, such as diabetes and obesity. 6 According to the Global Burden of Disease from 1990 to 2015, HBV and HCV accounted for 432, 000 liver cancer deaths (54%), alcohol for 245, 000 (30%), and other causes for 133, 000 (16%) deaths. In particular, 55% of all HCC cases worldwide are reported from China 38 due to the locally high prevalence of hepatitis B virus (HBV) infection.

As the second most common liver carcinoma following HCC, ICC accounts for around 15% of PLC cases with a high incidence of 2 per 100,000 population worldwide annually. 39 The most common risk factors for ICC are biliary tract diseases including choledochal cysts, cholelithiasis, choledocholithiasis, liver flukes, viral hepatitis, metabolic syndrome, and other risk factors including tobacco and alcohol use, and cirrhosis. 7 Recently, the incidence of ICC has been increasing more rapidly owing to risk factors 8 including increasing chronic liver disease and environmental toxins, and is found more often due to improved diagnostic tools and imaging. cholangiocyte differentiation, and has a poor prognosis. 40 cHCC-ICC is a rather rare tumor with an incidence rate less than 5%. 1 The poor prognosis associated with cHCC-ICC is due to the limited treatment options and difficulty of diagnosis. To date, the largest cohort analysis which included 529 patients diagnosed with cHCC-ICC between 2004 and 2014 across 18 registries 41 reported that the incidence of cHCC-ICC in men and women was 0.08 and 0.03 per 100,000 per year respectively, with the average age of 63 y at diagnosis. One-and five-year cause-specific survival rate for cHCC-ICC was 41.9% and 17.7%, respectively, with the median survival of 8 m.

Among racial groups, cHCC-ICCs are most common in Asian and Pacific islanders.

Obesity, nonalcoholic steatohepatitis and liver cirrhosis were observed in some cHCC-ICC cohorts 9, 10 and are potential risk factors for cHCC-ICC.

• HCC HCC shows a solid, trabecular and pseudoglandular pattern with a high density of tumor cells. It has three subtypes：well differentiated HCC，moderately differentiated HCC, and poorly differentiated HCC. [11] [12] [13] Well-differentiated HCCs are often small • ICC ICC can be divided into two subtypes: a small duct type which originates from small intrahepatic ductules with no or minimal mucin production, and a large bile duct type which arises from large intrahepatic ducts proximal to the bifurcation of the right and left hepatic ducts, with high mucin production ability. [14] [15] [16] Further, ICC shows three different growth patterns: mass-forming (MF), periductal infiltrating (PI), and J o u r n a l P r e -p r o o f intraductal growth (IG). 42 MF ICC is a firm, multilobulated, unencapsulated, white-gray tumor, owing to its extensive desmoplastic stroma. The PI subtype shows extensive infiltration along the intrahepatic hilum structure, and the IG subtype is usually restricted to tubes with papillary structures. MF ICC is the most common type associated with a poor prognosis while IG type is rare but has a favorable prognosis. 17 • cHCC-ICC Though the phenomenon of HCC and ICC being present in the same liver was first described in 1903. 17 cHCC-ICC was not systematically described until 1949, when it was classified into three subtypes depending on the location of HCC and ICC: type A (separate type) has separate nodules of hepatocellular and bile duct carcinoma; type B (combined type) shows contiguity with intermingling but with clearly defined areas; type C (mixed type) presents as intimate association without clear boundaries. 18 In 1985,

another classification system with three subtypes was established: Type I (collision tumors) -simultaneous occurrence of both HCC and ICC in the same patient; Type II (transitional tumors) -with an identifiable intermediate transition between HCC and ICC; Type III (fibrolamellar tumors) -which resembled the fibrolamellar variant of HCC but also contained mucin-producing pseudoglands. 19 Presently, the WHO 2010 classification is commonly used, in which cHCC-ICC is classified into two main types, the classic type and the SC type (subtypes with stem cell (SC) features), with the SC type subdivided into three subtypes including the typical subtype (TS), intermediate subtype (INT) , and cholangiolocellular type (CLC) 43 .

The lack of a unified classification system greatly adds to the difficulty for cHCC-ICC research and the clinicopathological characteristics of cHCC-ICC remain ill-defined.

cHCC-ICC can exhibit stem/progenitor cell phenotypes consisting of small cells with scant cytoplasm, hyperchromatic nuclei embedded within a thick, desmoplastic stroma, a high nuclear/cytoplasmic ratio, and the increased mitotic activity. 1 And the IHC (immunohistochemistry) identified stemness-related markers (KRT19, CD56, EpCAM,

Wide-scale genomic studies have revealed that hundreds of somatic DNA alterations accrue in HCC, including chromosome aberrations and mutations. High-level DNA amplifications are enriched in chromosome locations 6p21 and 11q13 location in HCC 44 , which occur in 5-10% of cases. Recently, some oncogenic genes were identified in the regions of frequent DNA gain. For example, LINC01138 is an oncogenic long intergenic non-coding RNA located in this region which has been identified as a driver of HCC. 45 VEGFA and CCND1/FGF19 have also identified in these regions and are potential therapeutic targets. 46 Loss of heterozygosity on chromosome 8p is a frequent event in HCC. 47 These DNA alterations are often associated with cancer progression due to the deletion of tumor suppressor genes. Intriguingly, in these regions, a variety of vulnerability genes have been recently identified. For example, TSLNC8 was characterized as a tumor suppressor gene on chromosome 8p12, the region that shows allelic loss in HCC and was shown to inhibit to the proliferation and metastasis of HCC. 48 The genetic mutations of HCC have been well-studied. Mutations in the TERT promoter occur in approximately 60% of cases and cause recurrent viral insertion of HBV. 49 Deletion mutations in TP53 are the most frequent genetic alterations, accounting for about 30% of cases [22] [23] [24] [25] [26] [27] [28] [29] , and are thought to be the initiating event driving the formation of precursor lesions. Mutated genes in WNT signaling (CTNNB1 and AXIN1) and chromatin remodeling (ARID1A) account for approximately 27-40% of cases. 22-29 Accumulation of activating mutations in oncogenes, including activation of AKT or mTOR and of the oxidative stress pathway activation, occurs throughout tumor progression, and could be potentially targeted with molecular therapies in the future. stem cell marker, is highly expressed in cHCC-ICC and is strongly associated with poorer prognosis. 36 Hence, Nestin may be a promising biomarker for cHCC-ICC.

4a. Resection, transplantation, local and regional therapies

The commonly used staging system for HCC is the Barcelona Clinic Liver Cancer staging system ( Figure 1 ). HCC in the very early stage or intermediate stage can be treated with the local regional therapies, which includes radiofrequency ablation (RFA), •

An accurate diagnosis is of paramount importance for the treatment of cHCC-ICC.

Currently, major hepatectomy is the optimal management for cHCC-ICC. 65 92 Currently, FOLFOX has regarded as the second-line treatment option.

Currently several phase II and III chemotherapy clinical trials are under way (Table 3) .

Combined therapy with chemotherapy shows promise in the treatment of CCA: 

Apatinib, a tyrosine kinase inhibitor targeting VEGFR-2, significantly prolonged OS and PFS in Chinese patients with advanced HCC who had previously been treated with Sorafenib and/or chemotherapy, according to the results of a randomized, placebo-controlled, phase III trial conducted in 31 sites in China. 115 Median OS was almost 2 months longer for patients who received Apatinib compared with patients receiving the placebo (8.7m vs 6.8m), and median PFS was more than 2 months longer (4.5m vs 1.9m). 115 The most common grade 3 or worse adverse events occurred at a rate of 69.2% in the Apatinib arm and 3.1% in the placebo arm. With the significantly prolonged OS and PFS and a manageable safety profile, Apatinib has potential to become a new second-line therapy for liver cancer.

Even with all these available treatments (Table1), the median PFS for HCC patients remains less than a year. Thus, novel treatment is still a critical unmet need for treatment of HCC. Based on the genomic profile and biomarkers reported in HCC, several clinical trials targeting various pathways are currently ongoing (Table 2) .

Recently, a first-in-human phase I study (NCT02508467) of Fisogatinib (BLU-554)an orally bioavailable inhibitor of human FGFR4 demonstrated its anti-tumor activity in HCC, and future validated that the aberrant FGF19-FGFR4 signaling pathway may J o u r n a l P r e -p r o o f be a driver event. 116 In addition, the TGF-β1 Receptor Type I Inhibitor Galunisertib also showed an acceptable safety and prolonged OS outcome in combination with Sorafenib in a phase II trial (NCT01246986). 117, 118 Other potential candidates including the cyclin-dependent kinases (CDKs) inhibitors regulating the cell cycle pathways -Ribociclib, Palbociclib, 119 (Table 3) , and some of which have made progress in the treatment of ICC (Table 1) .

The most promising target therapy for CCA identified in recent years is the inhibitor of the fibroblast growth factor (FGF) signaling pathway, which consists 22 members With the promising results of phase II, the phase III clinical trial of Pemigatinib is currently underway (NCT03656536).

Infigratinib (BGJ-398) was the first FGFR inhibitor investigated for treatment of CCA.

It is an oral drug which selectively binds to FGFR 2 and shows impressive anti-tumor efficiency and a manageable safety profile in participants with advanced FGFR-altered CCA (NCT02150967). 131 Sorafenib was withdrawn. 148 The efficacy of Sorafenib in cHCC-ICC needs to be further investigated in a large group of samples. can generate neoantigens which make the cancer cells susceptible to inhibition of the PD-L1/PD-1 interaction and sensitive to immunotherapy. 183 MSI is most commonly seen in colorectal and endometrial cancers, however, CCA has also been reported to exhibit MSI with a frequency above 10%. 184 

Although many clinical drugs have been approved or tested in advanced HCC and ICC, the median PFS and OS remain dismal. One of the reasons is the acquired drug resistance due to the intra-tumor heterogeneity or the continuous diversification during treatment which allows certain tumor cells to survival and eventually develop a drugresistant phenotype. This remains the huge hurdle for the long-term use of targeted therapies for PLC. 193, 194 It is therefore necessary to further explore the mechanism of drug resistance. Recently, Tang, J., et al. reported a novel somatic mutation in OCT4 (c.G52C) associated with Sorafenib resistance. 195 Further work in this vein will allow us to understand the mechanism and the exact gene mutation responsible for the drug resistance, allowing for targeting of specific mutation sites, thereby hopefully overcoming drug resistance.

Another challenge for targeted therapies in PLC is lack of precise targets and biomarkers. Unlike breast cancer, which has the precise biomarker HER2, PLC has a high degree of heterogeneity and genomic diversity and with no accurate biomarkers.

Although many high-frequency mutant genes such as TERT, TP53, CTNNB1, and KRAS have been confirmed in PLC, it is still not clear whether they play the role of "driver gene" or "passenger gene" in the progression of liver cancer, which limits the development of targeted drugs. There is therefore an unmet need to comprehensively understand the genomic architecture, define the mutation landscape, and identify novel biomarkers and driver genes in order to develop new therapeutic interventions. With J o u r n a l P r e -p r o o f this information, future clinical trials could employ precision medicine to treat patients based on specific genetic mutation and drivers. Another point of concern is that PLC has a high recurrence rate; more than 70% of patients will relapse within five years after surgery. 196 Thus, whether the genetic features remain the same in the primary and recurrent tumors is also worth exploring.

In recent years, immune checkpoint inhibitors ( Aside from these mainstream treatments, some novel therapies have also been proposed in the management of PLC. For example, René Bernards and his team recently elaborated some new idea about combined therapies by devising a "one -two punch" method (named after the effective combination of two rapid consecutive moves in boxing). 201 The "first punch" makes use of a specific mutations (like TP53) in tumor cells to specifically induce it to a certain state like cell senescence, and then the next "second punch" precisely removes aging tumor cells. Therefore, although these two drugs are not used at the same time, they have synergistic effect with reduced toxicity and high precision. 

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Public Summary 1. Primary liver cancer comprises hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), combined HCC-ICC (cHCC-ICC), which are markedly distinct in their epidemiology, clinical features and response to therapy

HCC is viral infection-related malignancy with specific histological features, whereas ICC is associated with chronic liver inflammation, showing more specific signatures

HCC is prone to respond to targeted therapy, immunotherapy and antiviral agents, whereas ICCs are benefit from chemotherapy, targeted therapy and immunotherapy

Combined cHCC-ICC subclass shows strong ICC-like features and is considered to be treated like ICC, whereas mixed cHCC-ICC subclass is shown to resemble HCC and is treated like HCC

We thank Zichen Xu for assistance in the preparation of the figures. This work was