Metastatic pancreatic cancer with activating BRAF V600E mutations: A case report

Abstract

BACKGROUND

Pancreatic cancer (PC) is a highly malignant tumor that is resistant to chemotherapy, radiotherapy and immunotherapy. Combination chemotherapy regimens are the standard first-line regimens for metastatic disease, with a median survival < 12 months. Although recurrent genomic alterations such as the BRAF V600E mutation have been reported in PC, evidence supporting the clinical effectiveness of molecularly guided targeted therapies is limited.

CASE SUMMARY

We report a case of a 33-year-old male who was referred to our department with weight loss of 5 kg in 2 months, anorexia and abdominal pain. Imaging showed extensive lesions involving the pancreas, liver, bones, muscles and lymph nodes accompanied by elevated carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA). Biopsy yielded a diagnosis of PC. Treatment with gemcitabine and nab-paclitaxel was initiated, but the disease progressed in < 2 months even though the patient’s general condition improved. Molecular testing revealed the presence of BRAF mutation. Dabrafenib/trametinib combination therapy was introduced, and the patient was treated for 2 months with a decrease in CA19-9 and CEA levels, but he died after 2 months of treatment.

CONCLUSION

BRAF alterations are infrequent in PC. This case highlights the significance of molecular profiling in patients with PC, especially in patients with a high tumor burden.

Key Words: Pancreatic cancer; BRAF gene mutation; Targeted therapy; Prognosis; Case report

Core Tip: Pancreatic cancer (PC) is an extremely aggressive malignancy, characterized by a 5-year survival rate of merely 11% and is highly resistant to chemotherapy, radiotherapy and immunotherapy. PC is largely defined by core driver gene mutations. BRAF mutations are rare, but important because of the availability of targeted drugs. We report a rare case of PC with a high tumor burden with BRAF V600E mutation. Despite the use of chemotherapy and targeted therapy, the patient’s outcome remained poor. This case highlights the significance of molecular profiling in patients with pancreatic tumors, especially in young patients with aggressive characteristics.

INTRODUCTION

Pancreatic cancer (PC) is an extremely aggressive malignancy with a 5-year survival rate of 11% and is highly resistant to chemotherapy, radiotherapy and immunotherapy[1-5]. Despite its high mortality, PC is uncommon, with an incidence of 8–12 cases per 100000 per year and a lifetime risk of 1.3%[6]. However, the global burden of PC has increased dramatically over the past few decades and is expected to remain a leading cause of cancer-related mortality (see Surveillance, Epidemiology, and End Results Program). The risk of death from PC rises significantly with age from < 2 deaths per 100000 person-years for individuals in the United States aged 35–39 years, to > 90 deaths per 100000 person-years for those aged > 80 years. As global health improves and life expectancy increases, the overall incidence of PC is also likely to rise[7].

Although genomic profiling is widely accessible, therapies approved by the United States Food and Drug Administration (FDA) for PC are primarily restricted to combination cytotoxic treatments, such as folinic acid, 5-fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX)[8], gemcitabine with nab-paclitaxel[9], and nal-irinotecan with fluorouracil[10]. Tumor antigen markers for programmed death protein (PD)-1 inhibitors and Trk inhibitors are scarce in PC (< 1%)[11-13]. Olaparib is still the sole targeted treatment available for a specific molecularly defined group of PC[14].

The potential of precision oncology has been realized for some types of cancer, such as lung cancer and melanoma, and has gradually promoted the development of other tumors. Recently, specific actionable targets have been recognized in PC, which is primarily characterized by mutations in key driver genes; KRAS (90%), TP53 (64%) and CDKN2A (17%) are commonly seen in PC, and BRAF alterations are less frequent (2%)[15]. Patients who have actionable molecular alterations can derive considerable benefit from receiving matched therapy. The median overall survival (OS) of patients with advanced PC who have actionable alterations receiving matched therapy is 1 year longer than those with actionable alterations receiving unmatched therapy, or those without actionable alterations[16]. BRAF mutations are rare, but important because of the availability of targeted drugs. The NCI-MATCH basket trial subprotocol H tested dabrafenib plus trametinib for BRAF V600E mutation tumors, with a 38% objective response rate and 11.4 months progression-free survival (PFS). This was one of the most successful basket trials[17]. In this comprehensive study, two patients with PC were enrolled and both presented with encouraging responses. They demonstrated disease control and significant tumor volume reduction. This finding provides valuable insights into potential treatment approaches and paves the way for further research in this challenging field. Based on the positive results, the FDA approved dabrafenib plus trametinib combination in pretreated cancers with BRAF V600E mutation[18]. Because of its low incidence, a prospective randomized phase 3 clinical trial of a BRAF mutation in PC is not feasible. Therefore, it is crucial to share real-world experiences through case reports to ensure that new biomarkers are appropriately utilized in some rare tumors.

This case report presents a man aged 33 years who presented with PC with a high tumor burden. Combination chemotherapy was discontinued after < 2 months because of further disease progression with new brain metastasis. Molecular testing revealed the presence of BRAF mutation. Targeted therapy was started with the oral dabrafenib/trametinib combination, and the patient was on therapy for 2 months, with a decrease in carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) level, but he died after 2 months. This case highlights the importance of molecular profiling in patients with pancreatic tumors, especially in young patients with aggressive tumors.

CASE PRESENTATION

Chief complaints

A man aged 33 years with no history of illness was referred to our department with weight loss and anorexia for 2 months.

History of present illness

The patient’s appetite was abnormal, and he had a weight loss of 5 kg over 2 months, accompanied by abdominal pain. His stools were normal, with no history of constipation or diarrhea.

History of past illness

The patient denied any past illness.

Personal and family history

The patient denied any family history of malignant tumors.

Physical examination

The patient’s height and weight were 172 cm and 54 kg, respectively. His body mass index was 18.25 kg/m², and body surface area was 1.61 m², and Eastern Cooperative Oncology Group performance status score was 2. Jaundice was not observed.

Laboratory examinations

Laboratory results included elevated CA19-9 level of > 10000 U/mL, CEA of 82.1 ng/mL, elevated white blood cell count of 29.88 × 10⁹/L, decreased hemoglobin of 108 g/L, elevated C-reactive protein of 145.3 mg/L, elevated serum creatinine of 138 μmol/L, elevated alanine aminotransferase of 51 U/L, elevated aspartate aminotransferase of 75U/L, and elevated total bilirubin of 28.3 μmol/L.

Imaging examinations

Ultrasonography revealed multiple masses in the liver. Positron emission tomography/computed tomography revealed a high tumor burden with malignant lesions involving the pancreas, liver, multiple bones, left supraspinatus, left adductor, multiple lymph nodes (bilateral neck, clavicle, mediastinum, bilateral hilum of the lung, abdomen, pelvis, and retroperitoneum), hydropericardium, hydrothorax, and splenomegaly. The tumor had infiltrated the liver diffusely, as shown in Figure 1. Computed tomography pulmonary angiography revealed a few emboli in the left lower lung. Liver biopsy detected adenocarcinoma. Immunohistochemical analysis revealed that the tumor was positive for cytokeratin (CK) 7, CK19, CK20, MutS Homolog (MSH) 2, MSH6, PMS1 Homolog 2, MutL Homolog 1 and Ki67 (60%) and negative for S100p, drosophila mothers against decapentaplegic protein 4, Thyroid Transcription Factor-1, NapsinA, Caudal type homeobox transcription factor 2, Cluster of Differentiation 20, PD-1 and PD-ligand 1, which suggested pancreatic origin.

Figure 1 Positron emission tomography/computed tomography of whole body and abdomen before treatment. A: Coronal bitmap of positron emission tomography/computed tomography (PET/CT) fusion image revealed high tumor burden with malignant lesions involving pancreas, liver, multiple bones, and multiple lymph nodes (bilateral neck, clavicle, mediastinum, bilateral hilum of lung, abdomen, pelvis and retroperitoneum; B: CT images revealed multiple low-density lesions in the liver; C: Cross-sectional PET/CT fusion image revealed multiple lesions with elevated ¹⁸F-fluorodeoxyglucose metabolism in liver and lumbar vertebra; D: PET image revealed multiple lesions with elevated ¹⁸F-fluorodeoxyglucose metabolism in liver and lumbar vertebra; E: Maximum intensity projection image revealed high tumor burden with malignant lesions involving pancreas, liver, multiple bones, and multiple lymph nodes (bilateral neck, clavicle, mediastinum, bilateral hilum of lung, abdomen, pelvis and retroperitoneum.

FINAL DIAGNOSIS

The patient was diagnosed with cTxN + M1 (8^th edition of the UICC-TNM classification) PC with liver, multiple bones, multiple lymph nodes and multiple muscle metastases, comorbid with pulmonary embolism, mild anemia, abnormal liver function, hydrothorax and hydropericardium.

TREATMENT

The Gem-nabP regimen was initiated, which consisted of intravenous gemcitabine at 1 g/m² on d 1 and 8 and nab-paclitaxel at 125 mg/m² on day 1 and 8 of a 21-day cycle. After the first course, the patient presented with grade 4 leukopenia according to the Common Terminology Criteria for Adverse Events version 5.0. In the second course, the dose of the chemotherapeutic drugs was reduced by 25%. There was no recurrence of leukopenia and the biochemical tests did not reveal any side effects. Because of bone metastases, desuximab was administered subcutaneously at 120 mg/months. The pulmonary embolism was treated with rivaroxaban at 20 mg once daily.

After two courses of chemotherapy, the patient’s general condition improved, and his transaminase levels returned to normal and CEA level decreased from 82.1 to 10.5 ng/mL, but CA19-9 remained > 10000 U/mL. Gem-nabP regimen was stopped after three cycles because of further disease progression, when a seizure occurred, and new multiple intracranial metastases (Figure 2), hydrothorax and ascites, peritoneal metastasis, and carcinomatous lymphangitis were identified on imaging, while the metastatic liver and lymph node lesions were reduced, as shown in Figure 3. Comparing Figure 1 and Figure 3, it can be observed that both the volume and the number of metastatic liver lesions were reduced. Thoracentesis was performed to drain the hydrothorax. Exfoliative cytology of the hydrothorax suggested an adenocarcinoma.

Figure 2 Magnetic resonance imaging of multiple intracranial metastases after first-line chemotherapy. A: Magnetic resonance imaging (MRI) T1-weighted image revealed multiple lesions in the frontal and parietal regions; B: MRI T1-weighted image revealed multiple lesions in the basal ganglia; C: MRI T1-weighted image revealed multiple lesions in the temporal lobe and brainstem; D: MRI T1-weighted image revealed multiple lesions in the brainstem and cerebellum.

Figure 3 Magnetic resonance imaging and computed tomography of abdomen after treatment with first-line chemotherapy. A: Magnetic resonance imaging T2-weighted image revealed multiple lesions in the liver; B: Computed tomography image revealed multiple low-density lesions in the liver.

Genomic testing (AmoyDx Company^@, Xiamen, China) revealed a BRAF V600E mutation in exon 15 with an abundance of 61.62% as class 1, Myc gene amplification with 55.93 copies as class 2, tumor protein 53 gene mutation in exon 7 as class 2, BRCA 1/2 wild type, and microsatellite-stable status by next-generation sequencing.

Targeted therapy was initiated with oral dabrafenib 150 mg twice daily and trametinib 2 mg once daily. Oral antiepileptic drugs were introduced, which consisted of levetiracetam (0.5 g) twice daily and sustained-release valproic acid (500 mg) twice daily, and no seizures occurred. Whole-brain palliative radiotherapy was performed using volumetric modulated arc therapy. The whole brain was used as the clinical target volume, and 3000 cGy/10 fractions was planned, during which mannitol dehydration was administered. After dabrafenib/trametinib combination treatment, the patient presented with grade 1 vomiting and fatigue. Routine blood and biochemical tests did not reveal any side effects. One and a half months after dabrafenib/trametinib combination treatment, CA19-9 level decreased from > 10000 to 9284 ng/mL and CEA from 10.5 to 3.4 ng/mL. Unfortunately, due to the patient's death, no images were obtained after the targeted therapy.

OUTCOME AND FOLLOW-UP

After 2 months of treatment, the patient died at home during his sleep. His family members refused an autopsy. The OS was 4 months.

DISCUSSION

PC is highly malignant and has limited treatment options. Combination chemotherapy regimens, such as Gem-nabP and FOLFIRINOX, are the standard first-line regimens for metastatic disease, with a median survival < 12 months. To tailor therapy effectively, it is essential to clarify the molecular subtypes and comprehend both intertumoral and intratumoral heterogeneity. In a retrospective analysis of The Know Your Tumor program, patients receiving molecularly matched therapy had a 6-mo extension in median PFS and a 1-year OS benefit compared with those who only received unmatched therapies[16]. These real-world outcomes suggest that the adoption of molecularly guided treatments can have a substantial effect on the survival of patients with PC. It is advised that all patients with locally advanced or metastatic disease undergo somatic molecular testing using tumor biopsies or cell-free DNA if a biopsy is not possible. Additionally, germline testing for hereditary genetic mutations is recommended for all patients who have recently been diagnosed with PC[18]. However, one real-world study showed a gap in the implementation of National Comprehensive Cancer Network (NCCN) guideline-directed genetic testing in PC patients, as only a third underwent testing, suggesting the need for systematic processes to facilitate testing[19].

PC is largely defined by core driver gene mutations. KRAS mutations are present in 90% of cases. KRAS wild-type status is found in 10% of PC cases and can be as high as 20% in younger patients. This status is associated with various targetable alterations, such as high microsatellite instability (MSI-high), high tumor mutational burden, BRAF mutations, ERBB2 amplification, and fusions involving NRG1, FGFR1-3, ALK, ROS, RET, and NTRK1-3[12]. KRAS^G12C inhibitors have demonstrated effectiveness in cancers with G12C mutations, and new pan-RAS and G12D inhibitors are currently undergoing clinical trials (NCT03785249, NCT04185883). Abnormalities in germline or somatic DNA damage repair are found in 5% to 10% of patients with PC and these patients are likely to respond positively to treatments involving DNA-damaging agents and maintenance therapy using poly-ADP ribose polymerase inhibitors such as olaparib[14]. Fewer than 1% of PC exhibit MSI-high status and are responsive to immune checkpoint inhibitors. While BRAF V600E mutations, as well as RET and NTRK fusions, are present in less than 1% of patients with KRAS wild-type PC, these alterations can be effectively treated using FDA-approved targeted therapies.

Accumulating data suggest that BRAF V600E-positive PC may benefit from a range of treatment strategies, including single-agent BRAF inhibitors, combined BRAF and MEK inhibitors, and MEK inhibitors combined with chemotherapy. A Phase 2 basket study evaluating vemurafenib in solid tumors harboring BRAF V600E mutations demonstrated that vemurafenib resulted in an approximately 20% reduction in the diameter of target lesions and disease stability for > 6 months in one of two patients with PC[20]. In another phase 2a basket study, four PC patients with BRAF alteration received vemurafenib monotherapy, but only one patient with a BRAF fusion achieved an objective response[21]. The specific BRAF variants in the other three patients and detailed outcome data have not been published. One study indicated that a patient with BRAF V600E-mutated PC exhibited a sustained response to treatment with dabrafenib and trametinib[22]. Furthermore, in a larger cohort, two patients with advanced BRAF V600E-mutated PC achieved prolonged partial responses following treatment with dabrafenib and trametinib[23]. Several additional case reports document clinical benefits from MAPK pathway inhibitors in BRAF V600E-driven PC[24-26]. Most of these case reports have noted disease sustained remission lasting > 6 months. Inn a comparable case report to ours, the patient exhibited a reduction in CA19-9 levels following 1 week of targeted therapy; however, the patient ultimately succumbed to intestinal perforation, which precluded the possibility of conducting an imaging assessment[27]. All these reports on BRAF alterations in PC strongly suggest the potential benefits of targeted therapy, but more data are needed to better define the extent of efficacy and the optimal treatment strategies[28]. Further preclinical investigations and collaborative, multicenter clinical trials are essential to enhance our understanding of this rare subtype of PC and to determine the most effective therapeutic strategies.

The patient in this case was only 33 years old and had a high tumor burden and rapid disease progression. Genetic testing suggested the presence of a BRAF V600E mutation. The disease progressed rapidly after the first-line Gem-nabP regimen despite an improvement in the patient’s general condition; the PFS of first-line treatment was only 1.8 months. The dabrafenib/trametinib combination was introduced as the second-line regimen; even though the CA19-9 level decreased, the patient died within 2 months, and the OS was 4 months. The patient’s treatment strategy was consistent with the NCCN guideline[29] recommendation of combination chemotherapy, such as Gem-nabP and FOLFIRINOX, as first-line regimens for PC with BRAF mutations, and BRAF/MEK inhibitors as second-line treatment when the disease progresses. However, combination chemotherapy and dabrafenib/trametinib did not result in long-term survival in our patient, possibly because of the high tumor burden and multiple intracranial metastases or the outgrowth of BRAF V600E-negative and/or -resistant clones. PC features a prominent stromal microenvironment with marked cellular and spatial heterogeneity that meaningfully affects disease biology and treatment resistance[30]. BRAF gene mutations lead to sustained cell proliferation and uncontrolled growth, and the specific isoform and tumor context influence sensitivity to targeted therapeutics[28]. At present, the mechanism of drug resistance in PC has not been fully elucidated, and more studies are needed to explore the mechanism of drug resistance. It is not known whether a better outcome will be achieved if dabrafenib/trametinib treatment is initiated as the first-line treatment. With the development of precision medicine and increasing medical evidence for targeted drugs, the use of targeted therapies in first-line therapy may be considered in the future.

CONCLUSION

This report describes a 33-year-old PC patient with a BRAF gene mutation and a high tumor burden. Combination chemotherapy and BRAF/MEK inhibitors were introduced as first-line and second-line treatment regimens, respectively; however, they did not result in long-term survival. This case study highlights the importance of identifying targetable genetic alterations in PC, specifically in young patients with high tumor burden.