Intrahepatic cholangiocarcinoma patient with epidermal growth factor receptor exon 19 deletion unresponsive to Afatinib monotherapy: a case report

Abstract

Background

The efficacy of epidermal growth factor receptor EGFR tyrosine kinase inhibitors in cholangiocarcinoma (CCA) patients is still unknown. Here, we report a 67-year-old CCA patient with EGFR exon 19 deletion receiving afatinib treatment.

Case description

A 67-year-old male was referred to our hospital due to persistent abdominal pain for 3 months. Abdominal computed tomography showed a tumor with a diameter of 92 mm in the left liver with multiple intrahepatic metastases. Immunohistochemistry revealed that tumor cells were positive for CK7 and CK19, and negative for hepatocyte and CDX- 2. A pathological diagnosis of intrahepatic CCA was made. Since the patient declined standard chemotherapy, afatinib was administered as the first-line treatment. Upon disease progression, apatinib was introduced. Unfortunately, the patient ultimately succumbed to hepatic failure, with a total survival of 1.8 months.

Conclusion

In this report, the CCA patient with EGFR exon 19 deletion was unresponsive to afatinib treatment. However, genetic testing may be still worthwhile for CCA to increase the possible treatment options.

Introduction

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies originating from the biliary system [1]. Intrahepatic cholangiocarcinoma (ICC) represents the second most prevalent primary liver malignancy, comprising 10–20% of all cases of primary liver cancer [2]. CCA is highly malignant. It has been reported that early-stage CCA patients have a high postoperative recurrence, which is associated with an unfavorable prognosis [3, 4]. The standard first-line therapeutic approach for advanced CCA is the combination of gemcitabine with platinum-based chemotherapy, a regimen whose efficacy is well-established and supported by numerous phase II single-arm trials, as well as the control arms of randomized trials, including the landmark studies [5, 6].

CCA is at the forefront of a therapeutic transformation, particularly with the emergence of immunotherapies. These novel treatments have expanded the arsenal of therapeutic options but also introduce new challenges, such as immune-related neurotoxicities, including peripheral neuropathy and headaches, which necessitate careful management [7]. Immune checkpoint inhibitors have also been linked to rare adverse events, such as hearing loss, underscoring the importance of vigilant monitoring [8]. Recent advancements in biomarker research have identified the neutrophil-to-eosinophil ratio as a promising prognostic tool, offering a non-invasive method for risk stratification in CCA [9]. Additionally, targeted therapies focusing on FGFR and IDH mutations have shown early clinical promise, underscoring the potential of precision medicine in improving outcomes for these patients. The landscape of second-line treatments for biliary tract cancer (BTC) continues to evolve, with regimens such as mFOLFOX demonstrating potential survival benefits, highlighting the need for further investigation into innovative systemic treatments [10]. The BILCAP trial has also reshaped perspectives on adjuvant therapy for resectable BTC, offering new perspectives on treatment efficacy [11]. These advancements underscore the complex of CCA treatment and emphasize the importance of personalized strategies in this challenging malignancy.

It is well known that 50–70% of lung adenocarcinoma patients have epidermal growth factor receptor (EGFR) mutations [12]. EGFR tyrosine kinase inhibitors (EGFR-TKI) are the standard treatment for individuals diagnosed with advanced non-small-cell lung cancer (NSCLC) characterized by EGFR mutations [13], resulting in a substantial enhancement in PFS and the objective response rate (ORR) when compared with conventional chemotherapy [14]. Interestingly, EGFR mutations have been identified in 1%− 15% of CCA patients [15, 16]. Nevertheless, the effect of EGFR mutations on CCA is largely unknown, and the therapeutic efficacy of EGFR-TKI on CCA with EGFR mutation remains to be investigated.

In this report, we present a case of a patient diagnosed with CCA and harboring an EGFR mutation, who underwent afatinib monotherapy. Afatinib, an oral EGFR TKI, is approved for the treatment of NSCLC with specific EGFR mutations. This second-generation inhibitor irreversibly binds to EGFR, effectively blocking tumor growth and survival signals. Clinical studies have demonstrated its superiority in progression-free survival and response rates compared to chemotherapy in patients with activating EGFR mutations [17].

Case report

A 67-year-old male with a history smoking and alcohol consumption was referred to our hospital in February 2019 due to persistent abdominal pain for 3 months. Physical examination revealed a yellowish complexion and a mass in the right subcostal region. Abdominal computed tomography (CT) showed a tumor with a diameter of 92 mm in the left hepatic lobe with multiple liver metastases (Fig. 1A, B),staged as T4 N0M0 according to the Eighth Edition of Union for International Cancer Control [UICC] TNM Classification.

Fig. 1.

A, B Computed tomography of the abdomen revealed large low-density lesions in the left lobe of the liver, and the enhancement scan showed uneven enhancement. Multiple circular nodules of different sizes were seen in the right lobe of the liver, and the enhancement scan showed ring enhancement

Laboratory examinations revealed a normal level alpha-fetoprotein (1.27 ng/mL) and an elevated level carbohydrate antigen 19 - 9 (102.6 ng/mL).

Ultrasound-guided liver biopsy was carried out, and hematoxylin & eosin staining demonstrated that heterotypic epithelial cells were arranged in small nests, with irregular glandular-like structure and abundant and bright cytoplasm (Fig. 2A, B). Immunohistochemistry revealed that tumor cells were positive for CK7 (Fig. 3A) and CK19 (Fig. 3B), and negative for hepatocyte (Fig. 3C) and CDX- 2 (Fig. 3D). A pathological diagnosis of ICC was made.

Fig. 2.

Histopathology of the tumor. Hematoxylin–eosin staining showed that heterotypic epithelial cells were arranged in a small nest and irregular glandular-like structure. The cytoplasm was abundant and bright. A Magnification× 100, B magnification× 400

Fig. 3.

Immunohistochemistry staining of the tumor cells. The tumor cells were positive for CK7 (A) and positive for CK19 (B), but negative for hepatocyte (C) and CDX- 2 (D)

As part of the patient's diagnostic workup, genetic analyses were conducted, revealing an EGFR exon 19 deletion as determined by Amplification Refractory Mutation System (ARMS)-PCR (Fig. 4). The genetic testing performed focused on EGFR, ALK, and ROS1 mutations, as these were the only tests available in our hospital that were covered by insurance at the time. Consequently, the analysis did not include HER2 amplifications/mutations, FGFR alterations, IDH1 point mutations, RAS mutations, or PD-L1 expression.

Fig. 4.

EGFR19 deletion mutation was detected by the ARMS-PCR method

Although combination chemotherapy is the standard first-line treatment for advanced CCA, the patient expressed concerns about the potential toxicities associated with this therapy. Despite extensive discussions and efforts by our team to address these concerns and emphasize the survival benefits of chemotherapy, the patient ultimately decided against this approach. In addition, the patient had a history of smoking and alcohol consumption, along with poor liver function and advanced age. These factors were significant in the decision to forgo chemotherapy due to the anticipated high risk of complications.

Afatinib, an EGFR tyrosine kinase inhibitor, has efficacy in treating non-small cell lung cancer (NSCLC) with EGFR mutations. Based on this proven benefit, we hypothesized that afatinib could offer similar benefits in EGFR-mutated CCA, despite its lack of specific indications for CCA. Given the patient's refusal of standard chemotherapy, afatinib was considered a reasonable second-line treatment. The patient’s son provided written informed consent for this non-standard treatment, and approval for the off-label use of afatinib was obtained from our institutional review board. The patient was initiated on afatinib (40 mg po. every day) as the first-line treatment. However, after a month of treatment, the symptoms of abdominal distension and pain were getting worse. The CT scan revealed an 80%-increase in the longest diameter of the intrahepatic tumor (Fig. 5A, B). According to the Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1], the efficacy of the afatinib treatment was progressive disease, and the progression-free survival was 1 month. Following the failure of afatinib, the patient continued to refuse chemotherapy and requested oral medication. Consequently, we selected apatinib, an antiangiogenic agent, in an attempt to control disease progression. Despite these efforts, the patient died of hepatic failure with an overall survival of 1.8 months. A timeline summarizing the key events of the patient's clinical course is presented in Fig. 6.

Fig. 5.

A, B On day 30 after starting afatinib treatment, the CT scan showed an increase in tumor size

Fig. 6.

A timeline summarizing the key events of the patient's clinical course, including diagnosis, treatment decisions, and clinical outcomes

This study was approved by the ethical committee of the Affiliated Panyu Central Hospital of Guangzhou Medical University, Guangzhou, China (No. PYRC-2025 - 026- 01). Informed consent to Participate was obtained from the patient’s son. All regulations and measures of ethics and confidentiality have been handled in accordance with the Declaration of Helsinki and its later amendments.

Discussion

For advanced NSCLC, the EGFR exon 19 deletion represents the most prevalent activating mutation and is associated with TKI treatment sensitivity [18]. Different patterns of EGFR mutations have been identified in CCA patients [19, 20]. Gwak et al. [15] firstly reported that 3 out of 22 (13.6%) CCA patients had EGFR mutations, and all the 3 cases were EGFR exon 19 deletions (identical to EGFR exon 19 deletions in NSCLC). Leone et al. [19] showed that EGFR mutations were mainly T790M mutation in exon 20 and L858R mutation in exon 21 in the bile duct and gallbladder carcinoma. Wheler et al. also revealed that 1 out of 20 (5%) CCA patients had E804 K mutation in EGFR exon 20 [20]. However, it should be further elucidated whether these EGFR mutations are activating mutations.

Several studies on the efficacy of EGFR inhibitors have been conducted in CCA patients with abnormal EGFR expression. An uncontrolled phase II clinical trial has shown potential benefits from the use of EGFR inhibitors [21]. The trial suggests that these agents may offer clinical advantages when used as standalone treatments or in combination with Sorafenib. When evaluating afatinib as a treatment option, evidence from Lee's phase III clinical trial [22] and Leone's VECTIBIL trial [23] provides valuable support for the use of EGFR inhibitors in the management of CCA. Although the overall benefit in these studies, including patients with KRAS wild-type status, was limited or negligible, specific subgroups demonstrated notable outcomes. In Lee's trial, a statistically significant improvement in progression-free survival (PFS) was achieved in CCA patients receiving erlotinib (5.9 months vs. 3.0 months; hazard ratio [HR] 0.73, p = 0.049) [22]. Similarly, in Leone's VECTIBIL trial, the addition of panitumumab showed a trend towards enhanced overall survival (OS) advantage in ICC patients (15.1 months vs 11.8 months, p = 0.13) [23], although this result did not reach statistical significance. These findings highlight the potential utility of EGFR inhibitors in carefully selected patient populations. These results support the consideration of afatinib as a potential treatment option, particularly for patients who may belong to these responsive subgroups. Furthermore, the meta-analysis contained in the PICCA study [24] also confirmed the absence of an impact on overall survival, further emphasizing the importance of finding effective treatment options within specific patient populations. A phase I study also confirmed that afatinib, when combined with gemcitabine and cisplatin, did not yield any survival advantages in patients with advanced CCA [25]. However, most of the CCA cases selected in the above studies [21–25] were EGFR overexpression but not EGFR mutations. Only the phase I study [25] detected EGFR gene mutations in 9 patients, but none of them expressed mutations in Exons 18, 19, and 21.

As far as we are aware, this study marks the first instance of employing EGFR-TKI as the primary treatment for patients with CCA who display EGFR deletions. Unfortunately, the CCA patient with EGFR deletion in this report was unresponsive to afatinib treatment. There are several possible explanations for this outcome. Firstly, it is unclear whether EGFR mutations are driver mutations in CCA. Secondly, EGFR secondary mutations and bypass signaling activations may be also common resistance mechanisms, such as simultaneous mutations. Thirdly, CCA is a heterogeneous disease caused by a variety of etiologies, including viral and metabolic damage to the liver. Therefore, pathways such as EGFR may act differently in different subgroups, leading to differences in the efficacy of EGFR-TKIs.

A study using MassARRAY technology to evaluate 19 oncogenes in 94 resected CCA shows that 43% of the CAAs harbored at least one detectable mutation [16], suggesting that genetic testing for somatic mutations in CAA may increase personalized treatment options for molecular-targeted therapies. For instance, a multicenter, open-label, phase 2 study has reported the therapeutic potential of pemigatinib in CCA patients with FGFR2 fusions or rearrangements [26]. Nevertheless, it remains to be investigated which pattern of EGFR mutations in CCA patients may benefit from EGFR-TKI therapy. On the other hand, based on the phase III trials conducted in NSCLCs [27, 28], TKI combination chemotherapy or antiangiogenic therapy may improve the therapeutic outcomes. Therefore, more research on patient selection or treatment options should be conducted to improve the efficacy of targeted therapy in CCA patients.

The therapeutic failure in this case serves as an opportunity for reflection on the treatment strategies employed. Despite efforts to provide optimal care, the patient's poor prognosis, characterized by bulky hepatic disease, underscores the challenges of sequentially administering two treatment lines with unproven benefit. This approach resulted in limited salvage options following disease progression. To mitigate similar outcomes in the future, prioritizing more established therapies earlier in the treatment course should be considered. Additionally, integrating local treatment modalities such as radiofrequency ablation or transarterial chemoembolization could potentially improve therapeutic efficacy. Furthermore, enrolling patients in clinical trials may provide access to innovative therapies, ensuring a broader range of treatment options in cases with poor prognostic factors.

Conclusion

In conclusion, this study reported the treatment outcome of EGFR-TKI in CCA patient with EGFR mutation. Despite the poor treatment effect in this case, genetic testing may be still worthwhile for CCA to increase the possible treatment options.

Author contributions

Conception and design: Liping Lin, Xiaolong Cao Provision of study materials or patients: Caijiu Deng, Junming Huang, Qian Yu Collection and assembly of data: Caijiu Deng, Junming Huang, Qian Yu, Jianjun Han, Yuanxue Jiang Data analysis and interpretation: Caijiu Deng, Junming Huang, Qian Yu, Manuscript writing: All authors Final approval of manuscript: All authors.

Funding

Not applicable.

Data availability 

All the data and material were presented in the main paper.

Declarations

Ethics approval and consent to participate

This study was approved by the ethical committee of the Affiliated Panyu Central Hospital of Guangzhou Medical University, Guangzhou, China (No. PYRC- 2025 - 026 - 01). Informed consent to Participate was obtained from the patient’s son. All regulations and measures of ethics and confidentiality have been handled in accordance with the Declaration of Helsinki and its later amendments.

Consent for publication

Written informed consent was obtained from the patient’s son for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare no competing interests.