# Response to systemic treatments and survival of fibrolamellar carcinomas: An AGEO-SFCE French multicenter retrospective cohort

Xixi Ye-Tran, Mohamed Bouattour, Brice Fresneau, Anthony Turpin, Audrey Perret, Carole Vitellius, Romain Coriat, Jean Frederic Blanc, Marie Lequoy, Hélène Regnault, et al.

► To cite this version:

Xixi Ye-Tran, Mohamed Bouattour, Brice Fresneau, Anthony Turpin, Audrey Perret, et al. Response to systemic treatments and survival of fibrolamellar carcinomas: An AGEO-SFCE French multicenter retrospective cohort. Digestive and Liver Disease, 2025, 57 (7), pp.1495-1500. 10.1016/j.dld.2025.04.016. hal-05054551

HAL Id: hal-05054551

https://u-picardie.hal.science/hal-05054551v1

Submitted on 5 May 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
Oncology

Response to systemic treatments and survival of fibrolamellar carcinomas: An AGEO-SFCE French multicenter retrospective cohort

Xixi Ye-Tran<sup>a,*</sup>, Mohamed Bouattour<sup>b</sup>, Brice Fresneau<sup>c</sup>, Anthony Turpin<sup>d</sup>, Audrey Perret<sup>e</sup>, Carole Vitellius<sup>f</sup>, Romain Coriat<sup>g</sup>, Jean Frederic Blanc<sup>h</sup>, Marie Lequoy<sup>i</sup>, Hélène Regnault<sup>j</sup>, Daniel Pietrasz<sup>k</sup>, David Sefriou<sup>l</sup>, Thierry Lecomte<sup>m</sup>, Emilie Moati<sup>n</sup>, Olivier Caliez<sup>o</sup>, Eric Nguyen-Khac<sup>p</sup>, Thomas Walter<sup>q</sup>, Vincent Hautefeuille<sup>p,*</sup>

ARTICLE INFO

Article history:

Received 15 November 2024

Accepted 7 April 2025

Available online xxx

Keywords:

Chemotherapy

Fibrolamellar carcinoma

Response rate

Tyrosine kinase inhibitor

Overall survival

A B S T R A C T

**Introduction:** Fibrolamellar carcinomas (FLC) are rare and predominantly advanced hepatic malignancies, lacking a clear consensus on anti-tumor treatments (ATT). The primary objective of the study was to determine whether any ATT appeared to give favorable outcomes in terms of morphological objective response (ORR) and disease control (DCR) rate according to RECIST 1.1 criteria.

**Patients and methods:** This retrospective multicentric French cohort from 14 centers included 44 patients with histologically proven FLC who received at least one ATT (chemotherapy and/or tyrosine kinase inhibitors, TKI) and underwent at least one morphological evaluation.

**Results:** A total of 40 anti-tumor responses were analyzed after a first line treatment. No complete response was observed, with an ORR in 13 % of cases, a DCR in 55 % of cases and 45 % of disease progression. GEMOX regimen (n = 9) showed an ORR of 11 % and a DCR of 33 %; the combination of doxorubicin and platinum-based chemotherapy (n = 6) achieved an ORR of 33 % and a DCR of 83 %. For TKI, sorafenib (n = 10) and sunitinib (n = 3), there was no objective response, with a DCR of 40 % and 33 % respectively. The median and the 5-years overall survival were 3.3 years and 35 % (95 %CI=[0.23–0.54]) respectively.

**Conclusion:** FLC have a poor prognosis; ATT show mild response rate. Further approaches and personalized medicine seem to be an unmet need for patients with FLC and new treatments should be urgently developed.

© 2025 The Author(s). Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/))

<footnote><sup>a</sup> Gastroenterology Department, Grand Hôpital de l'Est Francilien (GHEF), Meaux, France</footnote>

<footnote><sup>b</sup> Liver Cancer Unit, Assistance Publique - Hôpitaux de Paris, Beaujon University Hospital, Clichy, France</footnote>

<footnote><sup>c</sup> Gustave Roussy, Department of Children and Adolescents Oncology, Villejuif, F-94805, France</footnote>

<footnote><sup>d</sup> Medical Oncology - Lille University Hospital - Lille, France</footnote>

<footnote><sup>e</sup> Medical Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France</footnote>

<footnote><sup>f</sup> Hepato-Gastroenterology Department, University Hospital, Angers, France</footnote>

<footnote><sup>g</sup> Department of gastroenterology and endoscopy, Hôpital Cochin, Université Paris Cité, Paris, France</footnote>

<footnote><sup>h</sup> Department of Digestive Oncology, Hôpital Haut-Lévêque, Bordeaux University Hospital, Pessac, France</footnote>

<footnote><sup>i</sup> Department of Hepatology, AP-HP, Saint-Antoine Hospital, F-75012, Paris, France</footnote>

<footnote><sup>j</sup> Department of Hepatology, Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Créteil, France</footnote>

<footnote><sup>k</sup> Department of Digestive, Oncological, and Transplant Surgery, Paul Brousse Hospital, Paris-Saclay University, Villejuif, France</footnote>

<footnote><sup>l</sup> Department of Gastroenterology, Digestive Oncology Unit, Rouen University Hospital, Rouen, France</footnote>

<footnote><sup>m</sup> Hepato-gastroenterology and Digestive Oncology, Tours University Hospital, Tours, France</footnote>

<footnote><sup>n</sup> Department of Gastroenterology and Digestive Oncology, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, Institut du Cancer Paris Carpem, Paris, France</footnote>

<footnote><sup>o</sup> Department of Hepato-gastroenterology, Assistance Publique, Hôpitaux de Paris, Pitié Salpêtrière University Hospital, Paris, France</footnote>

<footnote><sup>p</sup> Hepato-gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France</footnote>

<footnote><sup>q</sup> Gastroenterology and Digestive Oncology, Edouard Herriot University Hospital, Hospices Civils de Lyon, Lyon, France</footnote>

<footnote>* Corresponding author at: Department of Gastroenterology and Digestive Oncology, Amiens University Hospital, 80054, Amiens, France.
E-mail address: hautefeuille.vincent@chu-amiens.fr (V. Hautefeuille).</footnote>
Lay summary

Fibrolamellar carcinomas are very rare liver tumors, usually
affecting young people, often large and with vessels involve-
ment. The prognosis remains poor. There is no consensus on
antitumor treatment when the tumor is not operable. A com-
bination of oral drugs (sorafenib) and intravenous chemother-
apy shows encouraging results for tumor control, but new
therapeutic approach is needed.

# 1. Introduction

Fibrolamellar carcinoma (FLC), was first described by Edmond-
son in 1956 and is one of the primary hepatic malignant tumors.
It was formerly classified as a rare variant of hepatocellular carci-
noma (HCC) and represented 0.6 to 8.6 % of all HCC [1,2]. How-
ever, it is now recognized as a distinct entity with unique clini-
cal and histological characteristics compared to HCC. FLC predom-
inantly affects adolescents and young adults with a median age at
diagnosis of 21 years [3]. Unlike HCC, FLC occurs without chronic
liver disease such as hepatitis or cirrhosis [4] and no specific risk
factors for FLC development have been identified to date. The sex
ratio in FLC cases is reported to be 1:1 [3].

At diagnosis, clinical signs are not specific, routine biology is
often normal and alpha-fetoprotein is only increased in 10 % of
cases [3]. Radiologically, FLC is typically a single large tumor with
a central scar [5]. The diagnosis is confirmed by histology, shows
thick fibrous collagen bands surrounding tumor cells (hence the
term "fibrolamellar") with large eosinophilic polygonal cells [6].
Immunohistochemistry study (cytokeratin 7 and CD68) and a com-
patible morphology, confirm the diagnosis in 85-90 % of cases
[7-8]. Recently, a recurrent intrachromosomal deletion on chro-
mosome 19 was identified, leading to the fusion of DNAJB1 and
PRKACA genes and to the activation of the catalytic unit of Protein
Kinase A (PKA), and overexpression of Aurora Kinase A (AURKA).
This fusion is found in more than 95 % of the patients [9,10].

Prognosis of FLC is generally poor, as the disease is often diag-
nosed at an advanced stage (42.3 % to 60.0 % at stage IV of the
2010 AJCC classification), with a median OS (mOS) of 39 months
across all stage. Surgical resection represents the only potential cu-
rative option but relapse is frequent (33 % to 100 %) [3].

There is no consensus on the use of an active systemic
chemotherapy in locally advanced or metastatic FLC. In this study,
we aimed to evaluate the response to systemic treatments and
assess the survival outcome in a multicenter retrospective cohort
of FLC patients. The main objective was to determine whether an
anti-tumor treatment (ATT) appeared to yield more favorable re-
sults in terms of morphological objective response rate accord-
ing to RECIST 1.1 criteria in a population of locally advanced or
metastatic FLC receiving an ATT (including chemotherapy, tyrosine
kinase inhibitors or transarterial chemoembolization (TACE)) and a
least one morphological evaluation. Secondary objective was to an-
alyze outcome of FLC, clinical and morphological characteristics of
the population.

## 2. Patients and methods

2.1. Study population

The study included all consecutive patients diagnosed with a
histologically proven locally advanced or metastatic FLC, diagnosed
between 2004 and 2020, who had received at least one line of
anti-tumor treatment (chemotherapy, tyrosine kinase inhibitors or
both) and had at least one morphological evaluation of the disease

(response rate evaluated with a computed tomography (CT)-scan
or a magnetic resonance imaging (MRI)).

Patients were recruited from 14 French tertiary centers through
the AGEO (Association des Gastroentérologues Oncologues), the
SFCE (Société Française des Cancers de l'Enfant) networks and
pathology departments of university hospitals across France. Each
case was identified using the ADICAP codes: FF for the liver, and
A7X5 for the fibrolamellar character. Patients with a mixed type
tumor or uncertain diagnosis, as well as those without proper mor-
phological evaluation were excluded from the study.

Clinical data, biological markers (such as α-foetoprotein (AFP), Carcinoembryonic antigen (CEA), Carbohydrate antigen 19.9 (CA19.9), liver function tests), histopathologic features, DNAJB1-PRKACA fusion transcript (when available) as well as other somatic mutations identified through routine Next-generation sequencing (NGS, 35 genes panel mostly), were collected. Baseline radiological characteristics, anti-tumor regimens response rates, and progression-free survival (PFS) were also assessed. Overall response rate (ORR), sum of complete response (CR) and partial response (PR) and disease control rate (DCR), sum of CR + PR + stable disease (SD) for each treatment line were evaluated according to the RECIST 1.1 criteria. When not available, CT-scan or MRI has been reviewed and RECIST criteria calculated.

The study was conducted according to the Declaration of
Helsinki and French regulatory requirements (Commission Na-
tionale Informatique et Libertés registration number 2218839,
MR004 methodology). All patients alive at the time of the study
received appropriate information and gave their consent for anony-
mous data collection. In accordance with French national laws and
clinical research guidelines, this retrospective observational study
did not require formal ethics committee approval.

2.2. Objectives and statistical analysis

The primary objective of the study was to evaluate ORR and
DCR of systemic anti-tumor treatments in patients with locally ad-
vanced or metastatic FLC.

Secondary objectives were to evaluate clinical and morpholog-
ical characteristics of the study population, to assess overall sur-
vival (OS), progression free survival (PFS) and relapse free survival
for patients operated after initial locoregional or systemic ATT.

Continuous variables were expressed as median and range. Cat-
egory variables were expressed in percentage and total popula-
tion. OS was calculated from the date of initial diagnosis un-
til death from any cause, patients were censored if they were
alive at the date of last known status. PFS (for patients receiv-
ing systemic chemotherapy) was calculated from the date of first
line treatment and relapse free survival (RFS, for patients under-
going surgery during their medical management) from date of
surgery until date of first radiological progression. Median follow-
up was calculated using the reversed Kaplan-Meier non-parametric
method. OS, RFS and PFS were assessed using the Kaplan-Meier
non-parametric method, expressed in median with 95 % confidence
interval (95 %CI). Comparisons were performed using the log-rank
test. For all tests, *p* < 0.05 was considered to be statistically sig-
nificant. All statistical analyses were performed using R software
(R Development Core Team, Vienna, Austria; http://www.r-project.
org).

3. Results

3.1. Patients and tumor characteristics

Sixty-five consecutive patients were initially identified in 14 ter-
tiary centers in France. A total of 21 patients were excluded, 12 be-
<figure><img src="image_2.png" /><figcaption>**Fig. 1.** Flowchart of the study.</figcaption></figure>

<table><caption>**Table 1**

Baseline characteristics of the patients.</caption><thead><tr><th>Characteristic</th><th>Population (n = 44)</th></tr></thead><tbody><tr><td>Median age (range)</td><td>24 (13–62)</td></tr><tr><td>Female sex – no. (%)</td><td>26/44 (59.1 %)</td></tr><tr><td>WHO performance status – no. (%)</td><td></td></tr><tr><td>0–1</td><td>28/31 (90.3 %)</td></tr><tr><td>&gt;1</td><td>3/31 (9.7 %)</td></tr><tr><td>Underlying liver disease – no. (%)</td><td>0 (0 %)</td></tr><tr><td>AFP increased – no. (%)</td><td>5/44 (11.3 %)</td></tr><tr><td>Median size (cm) n = 43</td><td>10.2 (1.5–20.0)</td></tr><tr><td>Localisation – no. (%)</td><td></td></tr><tr><td>- Right liver</td><td>20/40 (50 %)</td></tr><tr><td>- Left liver</td><td>16/40 (40.0 %)</td></tr><tr><td>- Bilobar</td><td>4/40 (10.0 %)</td></tr><tr><td>Number of lesions – no. (%)</td><td></td></tr><tr><td>- Single</td><td>29/41 (70.7 %)</td></tr><tr><td>- Multiple</td><td>12/41 (29.3 %)</td></tr><tr><td>Vascular invasion – no. (%)</td><td>19/26 (73.0 %)</td></tr><tr><td>Lymph node involvement – no. (%)</td><td>25/35 (71.4 %)</td></tr><tr><td>Metastasis – no. (%)</td><td>12/34 (35.3 %)</td></tr><tr><td>Metastatic localization – no. (%)</td><td></td></tr><tr><td>- Lymph node</td><td>18/38 (47 %)</td></tr><tr><td>- Pulmonary</td><td>15/38 (39 %)</td></tr><tr><td>- Liver</td><td>14/38 (37 %)</td></tr><tr><td>- Peritoneal</td><td>10/38 (26 %)</td></tr><tr><td>- Others (bone, surreal)</td><td>3/38 (8 %)</td></tr><tr><td>Stage at diagnosis – no. (%)</td><td></td></tr><tr><td>- I</td><td>1/34 (2.9 %)</td></tr><tr><td>- II</td><td>0/34 (0 %)</td></tr><tr><td>- III</td><td>6/34 (17.6 %)</td></tr><tr><td>- IVa</td><td>13/34 (38.2 %)</td></tr><tr><td>- IVb</td><td>14/34 (41.2 %)</td></tr><tr><td>DNAJB1-PRKACA fusion– no. (%)</td><td>2/3 (66.6 %)</td></tr></tbody></table>

cause of histological misclassification as hepatocellular carcinoma and 1 mixed tumor, 8 patients with insufficient data (Fig. 1).

Overall, 44 patients were included. Median follow-up was 4.9 years. Baseline characteristics are detailed in Table 1. There were women in 59.1 % of cases, with a median age at diagnosis of 24 years (range, 13–62), 27 % being aged under 18 years. A vast major-

ity was in good general condition (90.3 % WHO performance status 0–1 at diagnosis).

FLC always occurred without underlying chronic liver disease or cirrhosis, and AFP was increased in only 11 % of cases with a median of 3 (range, 2–18000). The mean size was 10.2 cm (range, 1.5–20.0). Tumor distribution was right liver/left liver/bilobar is 50 %, 40 % and 10 % respectively. Multiple lesions were seen in 29 % of cases.

Vascular invasion on morphological examination was frequent (75.0 % of cases). At diagnosis, 79.4 % of patients were at stage IV: 38.2 % with exclusive lymph node involvement (stage IVa) and 41.2 % at a metastatic stage (stage IVb). The metastases mainly involved lymph node (47 %), lung (39 %), liver (37 %) and peritoneum (26 %). Every patient with multiple hepatic lesions were considered as having a liver metastatic spread. DNAJB1-PRKACA gene fusion testing was only performed in 3 patients and found positive in 2 cases [Table 1].

## 3.2. Response rate to first line anti-tumor treatment for advanced and metastatic FLC

As number of patients for chemosensitivity analysis is small, patients with locally advanced and metastatic were pooled for response rate analysis. Among all patients, morphological response assessment according to RECIST criteria was not possible for 4 patients (due to the absence of clear target lesions or absence of clear conclusion in radiological report mainly, all considered stable but without applicable RECIST criteria). Therefore, a total of 40 patients were kept in the per protocol response rate analysis including 6 with a locally advanced operated FLC and 34 with a locally advanced or metastatic palliative FLC.

The treatments administered included TACE (n = 3), systemic oral (n = 13), intravenous chemotherapy (n = 16) or a combination or chemotherapy and TKI (n = 8). Patients treated with TACE were all children and had a locoregional disease with a vascular involvement, in a neoadjuvant setting. For TACE, ORR is limited (33 %).

Response rate and type of treatment to first line (1 L) treatment are summarized in Table 2. Overall, no CR was observed, ORR
<figure><img src="image_3.png" /><figcaption>**Fig. 2.** Survival analysis. 2A: Overall survival of the cohort. 2B: Overall survival for operated and not operated patients. 2C: Relapse free survival for operated patients. 2D: Impact of neoadjuvant treatment on RFS for operated patients.</figcaption></figure>

<table><caption>**Table 2**
Response to first line antitumor treatment.</caption><thead><tr><th>Treatment</th><th>n</th><th>CR</th><th>PR</th><th>SD</th><th>PD</th><th>ORR</th><th>DCR</th></tr></thead><tbody><tr><td>Sorafenib</td><td>10</td><td>0</td><td>0</td><td>4</td><td>6</td><td>0 %</td><td>40 %</td></tr><tr><td>GEMOX</td><td>9</td><td>0</td><td>1</td><td>2</td><td>6</td><td>11 %</td><td>33 %</td></tr><tr><td>Doxorubicin - platinum</td><td>6</td><td>0</td><td>2</td><td>3</td><td>1</td><td>33 %</td><td>83 %</td></tr><tr><td>Doxorubicin - platinum- sorafenib</td><td>8</td><td>0</td><td>1</td><td>5</td><td>2</td><td>13 %</td><td>62 %</td></tr><tr><td>Sunitinib</td><td>3</td><td>0</td><td>0</td><td>1</td><td>2</td><td>0 %</td><td>33 %</td></tr><tr><td>TACE</td><td>3</td><td>0</td><td>1</td><td>1</td><td>1</td><td>33 %</td><td>67 %</td></tr><tr><td>FOLFOX</td><td>1</td><td>0</td><td>0</td><td>1</td><td>0</td><td>0 %</td><td>100 %</td></tr><tr><td>Doxorubicin - platinum-based</td><td>14</td><td>0</td><td>3</td><td>8</td><td>3</td><td>21 %</td><td>78 %</td></tr><tr><td>Overall</td><td>40</td><td>0</td><td>5</td><td>17</td><td>18</td><td>13 %</td><td>55 %</td></tr></tbody></table>

was achieved in 13 % of cases, DCR in 55 % of cases and 45 % had disease progression at first morphological evaluation. The doses of treatment regimens are detailed in Supplementary Appendix 1.

Among the cytotoxic chemotherapy regimens, the most commonly prescribed was GEMOX (n = 9) which yielded an ORR of 11 % and a DCR of 33 %. The combination of doxorubicin and platinum-based chemotherapy (n = 6) achieved an ORR of 33 % and a DCR of 83 %. For TKI, i.e. sorafenib (n = 10) and sunitinib (n = 3), no objective response was observed, but the DCR was 40 % and 33 %, respectively. Interestingly, two centers used a combination of chemotherapy and TKIs (doxorubicin-platin and sorafenib, n = 8) with an ORR of 13 % and a DCR of 62 % respectively. For TACE (n = 3), ORR was 33 % and DCR was 67 %. Finally, the only patient who received FOLFOX experienced stable disease.

### 3.3. Response rate to further lines of treatment

In the cohort, 86.3 % of patients received a 2nd line treatment, 52.3 % a 3rd line and 34.1 % a 4th line treatment.

Docetaxel (n = 3) as well as navelbin (n = 2) monotherapy showed no DCR. 5FU monotherapy, used in only one case, allowed stability at first evaluation. Sunitinib (n = 10) and regorafenib (n = 3) were evaluable after first-line, achieving 60 % and 0 % DCR respectively. Two patients were stable with lenvatinib and one pa-

tients had a partial response with cabozantinib. Seven patients received mTOR inhibitors: 4 patients under everolimus experiencing 2 stable disease and 3 under temsirolimus with 1 stable disease.

Finally, one patient had pembrolizumab and had a progressive disease at the first evaluation.

### 3.4. Survival analysis

All patients (n = 44) were included in the survival analysis, and results are presented in Fig. 2A. The mOS of the 44 cases in this cohort was 39.5 months. OS at 1, 3 and 5 years was 88 % (CI95 % = [0.78–0.98]), 54 % (CI95 % = [0.40–0.71]) and 35 % (CI95 % = [0.23–0.54]) [Fig. 2A]. The mOS of operated patients was better than that the non-operated patients, 55 and 15.5 months respectively (p = 0.02) [Fig. 2B].

Among the 24 patients who underwent surgery in this study, 23 experienced recurrence. After surgery, the median RFS was 11.0 months [Fig. 2C]. We further analyzed whether OS was different between the neoadjuvant group (n = 7) and the upfront surgery group (n = 17). There was no difference for OS regarding the 2 groups, as the neoadjuvant group experienced a 14.5 mOS, the latter having a similar mOS of 11.0 months (p = 0.2) [Fig. 2D].

## 4. Discussion

Fibrolamellar carcinoma is a rare malignant liver tumor with limited therapeutic options. The clinico-biological characteristics of our study population are globally similar to the data in the literature [3,11]. Paradoxically, FLC affects young adults in good general condition, is unique and without metastasis at diagnosis mostly, but shows aggressive features with bulky disease (median size of 10 cm) with macrovascular invasion (73 %) leading to high recurrence rate and poor prognosis as 23/24 patients in our cohort undergoing surgery relapsed. Overall, median survival is only 3.3 years and the median relapse-free survival after surgery was only 11 months.

To our knowledge, this is the largest study that has looked at the efficacy of anticancer treatments in FLC, with a nationwide,
population-based and unselected multicentric cohort from tertiary care centers. Few data in the literature can help make a choice between different therapeutic regimens, since only small series ranging from 3 to 21 cases [11–14] are published. A cohort of 53 cases treated between 1992 and 2008, mainly evaluating interferon α-2b (n = 27) showed 7 % CR, 22 % PR and 37 % SD [15].

The 2 most prescribed regimens in our cohort (sorafenib and GEMOX), may reflect management of FLC by hepatologists and pediatric oncologists since these 2 treatments have shown efficacy in the management of HCC [16–18]. Nevertheless, the DCR with these 2 regimens are relatively modest, below 40 %. The results of doxorubicin-platin in our series are similar to the SIOPEL cohort of 13 pediatric cases for which the DCR was 77 % [13]. The combination of a doxorubicin, platinum based regimen seems interesting, even if the impact of the addition of sorafenib is unclear (DCR of 83 % without sorafenib and 62 % with the tyrosine kinase inhibitors). Finally, TACE shows a good DCR (66 %) and may be an interesting treatment option in association with chemotherapy for neoadjuvant treatment in locally advanced bulby diseases.

In the analysis, median PFS for each regimen could not be calculated because of small sample size. The number of patients in our study is too small tough to make a conclusion regarding a more effective regimen and prospective studies are a high unmet need in determining an effective treatment for advanced FLC but may help the clinician to make a choice.

These tumors seem to respond, at least partially, to the treatments used in HCC. Their hypervascular aspect makes the use of either anti-angiogenics or intra-arterial treatment legitimate. A combination of anti-PD(L)1 therapy or even a triple combination of cytotoxic + anti-PD(L)1 + anti-angiogenic therapy could be a game changer. Recently, Kent et al. presented at ASCO 2023 the efficacy of a triple combination of lenvatinib and nivolumab +/- gemcitabine. In the neoadjuvant setting (n = 14), they reported an ORR of 40 % and a DCR of 87 %; for locally advanced and metastatic FLC (n = 17), the ORR was 41 % and the DCR 100 % [19,20].

As in gastrointestinal stromal tumors, which historically proved to be resistant to chemotherapy and whose prognosis has been drastically improved by imatinib [21], chemoresistance of FLC warrants new therapeutic approaches to overcome their poor prognosis. As the DNAJB1-PRKACA fusion transcript leads to overexpression of AURKA, inhibition of this kinase seemed promising. However, a recent study provided no rationale as a single agent for the use of ENMD-2076, an oral selective AURKA inhibitor [22] with a low ORR (3 %) and short survival with a mPFS of 3.9 months. Despite a strong preclinical rationale for inhibition of AURKA, this negative result may be explained by the sole inhibition of AURKA. A therapeutic approach combining multiple blockade may be the key to overcome resistance. Furthermore, the DNAJB1-PRKACA fusion may lead to activation of other unknown oncogenic pathways, which could therefore be targeted. One patient in our study was treated with a combination of gemcitabine and an aurora kinase inhibitor in a phase I study. Unfortunately, this combination failed to control the disease. In another phase II randomized trial, mTOR (everolimus) +/- aromatase inhibitors also failed to improve survival of advanced FLC [23]. New therapeutic approaches are ongoing, with the combination of immune checkpoint inhibitors (nivolumab and ipilimumab) and a DNAJB1-PRKACA peptide vaccine (NCT04248569).

This cohort has major limitations. Number of patients in each group are small, and comparison between the different treatment regimen for ORR or for survival analysis were not possible. Moreover, management of FLC across all centers were very heterogeneous (some having chemotherapy or TKI alone, some having both treatments) and standardized management in prospective cohorts are warranted. Furthermore, the retrospective design in

these rare cancers often leads to an information bias with missing data.

## 5. Conclusion

Fibrolamellar carcinomas are rare, show modest response to usual anticancer treatments and have a poor prognosis. Traditional treatments (cytotoxic chemotherapy and TKIs) are not very active, warranting development of new molecules or combinations targeting PKA/AURKA pathway, as FLC tumorigenesis is driven by DNAJB1-PRKACA gene fusion and as most FLC harbor a low frequency of other targetable mutations [24].

## Additional informations

The authors received no specific funding for this work and this research did not receive any specific grant from public funding agencies, commercial or not-for-profit sectors.

The authors would like to thank all participating authors for their contributions, and the Association des GastroEntérologues Oncologues (AGEO) for English language corrections funding.

This study was presented in e-publication at the 2022 ASCO Congress in Chicago (DOI: 10.1200/JCO.2022.40.16_suppl.e16194).

This study was performed in accordance with the ethical principles of the Declaration of Helsinki and French regulatory requirements.

Data are the property of VH and the AGEO and are not available.

## Conflict of interest

MB has received honoraria as a speaker or in an advisory role from Bayer, BMS, Sirtex medical, Eisai, Roche, Astra Zeneca.

AT reports personal fees from Servier, Viatris, Incyte Bioscience, BMS, Merck and grants and personal fees from AstraZeneca and MSD outside the submitted work.

RC has received honoraria as a speaker or in an advisory role from Ipsen, Novartis, Pierre Fabre, Amgen.

JFB: Bayer, Ipsen, Roche, Astra-Zeneca, MSD

HR: Boston, Sirtex

TL reported an advisory role with Amgen, Chugai, Bristol Myers Squibb, Merck Serono, Deciphera, Pierre Fabre, Servier, Astra Zeneca, BMS, Advanced Accelerator Applications, IPSEN, Lilly and Bayer outside of the submitted work; receiving grants from LEO Pharma and Pierre Fabre outside of the submitted work.

EM: Advisory board for Gilead, Lilly

TW reported an advisory role with Adacap, OranoMed, Terumo, Sirtex, and ITM outside of the submitted work; receiving fees for educational meeting from Incyte, Bristol Myers Squibb, Pierre Fabre, Servier, Astra Zeneca, Adacap, IPSEN, and MSD; receiving grants from Biodena, Adacap, Ipsen and Roche outside of the submitted work.

VH has received honoraria as a speaker or in an advisory role from AAA, Amgen, Ipsen, Deciphera, Merck KgA, Pierre Fabre, Servier

The other authors have nothing to declare.

## Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.dld.2025.04.016.

## References

[1] Njei B, Konjeti VR, Ditah I. Prognosis of patients with fibrolamellar hepatocellular carcinoma versus conventional hepatocellular carcinoma: a systematic review and meta-analysis. Gastrointest Cancer Res 2014;7:49–54.
[2] Ang CS, Kelley RK, Choti MA, Cosgrove DP, Chou JF, Klimstra D, et al. Clinicopathologic characteristics and survival outcomes of patients with fibrolamellar carcinoma: data from the fibrolamellar carcinoma consortium. Gastrointest Cancer Res 2013;6:3-9.

[3] Mavros MN, Mayo SC, Hyder O, Pawlik TM. A systematic review: treatment and prognosis of patients with fibrolamellar hepatocellular carcinoma. J Am Coll Surg 2012;215:820-30.

[4] Kassahun WT. Contemporary management of fibrolamellar hepatocellular carcinoma: diagnosis, treatment, outcome, prognostic factors, and recent developments. World J Surg Oncol 2016;14:151.

[5] Smith MT, Blatt ER, Jedlicka P, Strain JD, Fenton L. Best cases from the AFIP: fibrolamellar hepatocellular carcinoma. Radiographics 2008;28:609-13.

[6] Craig JR, Peters RL, Edmondson HA, Omata M. Fibrolamellar carcinoma of the liver: a tumor of adolescents and young adults with distinctive clinicopathologic features. Cancer 1980;46:372-9.

[7] Eyken PV, Sciot R, Brock P, Daele MCV, Ramaekers FCS, Desmet VJ. Abundant expression of cytokeratin 7 in fibrolamellar carcinoma of the liver. Histopathology 1990;17:101-7.

[8] Garg R, Srinivasan R, Dey P, Singh P, Gupta N, Rajwanshi A. Utility of cytokeratin 7 immunocytochemistry in the cytopathological diagnosis of fibrolamellar hepatocellular carcinoma. J Cytol 2018;35:75-8.

[9] Honeyman JN, Simon E, Robine N, Chiaroni-Clarke R, Darcy DG, Lim I, et al. Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science 2014;343:1010-14.

[10] Cao BH, Lu TW, Martinez Fiesco JA, Tomasini M, Fan LX, Simon SM, et al. Structures of the PKA R1α holoenzyme with the FLHCC driver J-PKAcα or wild type PKAcα. Structure 2019;27:816-28 e4.

[11] Kaseb AO, Shama M, Sahin IH, Nooka A, Hassabo HM, Vauthey JN, et al. Treatment outcome and prognostic indicators in 94 cases of fibrolamellar hepatocellular carcinoma. Oncology 2013;85:197-203.

[12] Maniaci V, Davidson BR, Rolles K, Dhillon AP, Hackshaw A, Begent RH, et al. Fibrolamellar hepatocellular carcinoma - prolonged survival with multimodality therapy. Eur J Surg Oncol 2009;35:617-21.

[13] Weedaa VB, Murawskib M, McCabec AJ, Maibachd R, Brugièrese L, Roebuck D, et al. Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma - results and treatment recommendations from the Childhood Liver Tumour Strategy Group (SIOPEL) experience. Eur J Cancer 2013;49:2698-704.

[14] Hammond WJ, Lalazar G, Saltsman JA, Farber BA, Danzer E, Sherpa TC, et al. Intracranial metastasis in fibrolamellar hepatocellular carcinoma. Pediatr Blood Cancer 2018;65:e26919.

[15] Patt YZ, Hassan MM, Lozano RD, Brown TD, Vauthey JN, Curley SA, et al. Phase II trial of systemic continuous fluorouracil and subcutaneous recombinant interferon alfa-2b for treatment of hepatocellular carcinoma. J Clin Oncol 2003;21:421-7.

[16] Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-90.

[17] Zaanan A, Williet N, Hebbar M, Dabakuyo TS, Fartoux L, Mansourbakht T, et al. Gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma: a large multicenter AGEO study. J Hepatol 2013;58:81-8.

[18] Louafi S, Boige V, Ducreux M, Bonyhay L, Mansourbakht T, de Baere T, et al. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC): results of a phase II study. Cancer 2007;109:1384-1390.

[19] Kent P, Schadde E, Fisher O, Cornelius A, Estberg E, Ellison J, et al. Nivolumab and lenvatinib combination for fibrolamellar carcinoma. J Clin Oncol 2022;40(16_suppl) 4111-4111.

[20] Kent P, Tasse J, Schadde E, Kato T, Humar A, Fisher O, et al. Early experience with nivolumab, gemcitabine, and lenvatinib for fibrolamellar hepatocellular carcinoma. J Clin Oncol 2023;41(16_suppl) 4076-4076.

[21] Demetri G, von Mehren M, Blanke C, Van den Abbeele A, Eisenberg B, Roberts P, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472-80.

[22] Abou-Alfa GK, Mayer R, Venook AP, O'Neill AF, Beg MS, LaQuaglia M, et al. Phase II multicenter, open-label study of oral ENMD-2076 for the treatment of patients with advanced fibrolamellar carcinoma. Oncologist 2020;25:e1837-45.

[23] Abou-Alfa G, Mayer RJ, Cosgrove D, Capanu M, Choti M, Atreya CE, et al. Randomized phase II study of everolimus (E), leuprolide + letrozole (LL), and E + LL (ELL) in patients (pts) with unresectable fibrolamellar carcinoma (FLC). J Clin Oncol 2015;33(15_suppl):e15149.

[24] Kastenhuber E, Craig J, Ramsey J, Sullivan K, Sage J, de Oliveira S, et al. Road map for fibrolamellar carcinoma: progress and goals of a diversified approach. J Hepatocell Carcinoma 2019;6:41-8.