Abstract
Background/Aim: Pancreatic ductal adenocarcinoma (PDAC) is a malignancy that typically portends a poor prognosis, with a median overall survival ranging from eight to twelve months in patients with metastatic disease. Novel modalities of therapy, primarily targeted therapy, are now considered for patients with targetable mutations, such as BRAF mutations based on next generation sequencing. BRAF mutations specifically within pancreatic adenocarcinoma remain rare with an incidence of approximately 3%. Previous research on BRAF mutated pancreatic adenocarcinoma is extremely scarce, limited primarily to case reports; therefore, little is known regarding this entity. Case Report: We seek to contribute to prior literature with the presentation of two cases of patients with BRAF V600E + pancreatic adenocarcinoma, who did not have a favorable response to initial systemic chemotherapy and were both subsequently treated with targeted therapy (dabrafenib and trametinib). Each of the patients has sustained a favorable response and there is no evidence of progression thus far on dabrafenib and trametinib, highlighting the potential benefit of targeted therapy in these patients. Conclusion: These cases emphasize the importance of early next generation sequencing and the consideration of BRAF targeted treatment in this patient population, especially if a response to initial chemotherapy is not sustained.
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease that will be the second leading cause of cancer-related deaths by the year 2030 with a 5-year survival rate of 11% (1), rendering it a malignancy with dismal prognosis. Treatment is often limited to neoadjuvant chemotherapy followed by surgical resection if diagnosed at an early stage and anatomically feasible; palliative chemotherapy is pursued in advanced disease. Notably, post pancreaticoduodenectomy, the 5-year survival rate is 10% in node positive patients (2) and 30% in node negative patients (3), highlighting the aggressive nature of this disease. Randomized controlled trials have demonstrated a benefit for chemotherapy in the adjuvant setting (4); however, most patients relapse within 2 years. The median overall survival for patients with metastatic disease eligible for systemic chemotherapy ranges from eight to twelve months. Numerous drugs have been added to the cancer therapy armamentarium of various malignancies due to the identification of actionable mutations on next generation sequencing (NGS) of tumors. BRAF mutations, typically V600E, are rare and present in only 3% of advanced pancreatic adenocarcinoma cases (5-7). These mutations tend to be highly resistant to standard chemotherapy. Given the paucity of these mutations, the literature for BRAF mutation positive pancreatic cancer is restricted primarily to case reports. However, there is some evidence that initiation of BRAF inhibitors (BRAFi), such as dabrafenib, has resulted in disease stability, regression and/or prolonged survival rates. We present two cases with BRAF V600E+ pancreatic adenocarcinoma treated with BRAFi, ultimately leading to partial response. We seek to add to the growing literature on BRAF mutations in pancreatic cancer and encourage consideration of early NGS and consideration of BRAFi especially in the subset of patients who do not respond to standard initial chemotherapy.
Case Report
Patient 1. A 75-year-old female with a past medical history of hypertension, type 2 diabetes mellitus and osteoporosis initially presented with complaints of unintentional weight loss (10 pounds in one month) and painless jaundice. Initial work up was significant for elevated liver enzymes (AST 446 U/l, ALT 358 U/l), total bilirubin of 8.6 mg/dl, alkaline phosphatase 550 U/l, and Hb 11.4 mg/dl. A computed tomography (CT) scan showed pancreatic duct dilation and cystic focus in the body of the pancreas measuring 2.3×2.2 cm as shown in Figure 1. CA 19-9 at this time was noted to be 1205 U/ml. The patient was referred to gastroenterology for an endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP), which was significant for an irregular mass in the pancreatic head measuring 2.0×2.9 cm. Multiple peripancreatic lymph nodes were also enlarged, with the largest measuring 1.2×2.1 cm. A metal stent was placed in the stenotic region of the lower one-third common bile duct. Fine needle biopsy from the pancreatic mass and lymph nodes was completed and it was shown to be positive for invasive ductal adenocarcinoma.
Initial CT scan of Patient 1 showing disease burden with cystic dilation in pancreatic body measuring 2.3×2.2 cm.
As there was no vascular invasion noted on imaging or metastatic disease, the cancer was deemed to be resectable, and the patient was started on neoadjuvant chemotherapy with four cycles of gemcitabine nab-paclitaxel. She sustained a partial treatment response based on imaging with decreased size of pancreatic cystic mass to 1.9 cm, and decreased lymph node to 0.6 cm. CA 19-9 decreased to 48 U/ml at this time. She subsequently underwent a Whipple’s procedure. Pathology showed mixed acinar-ductal carcinoma of the pancreas measuring 1.9 cm. Of note, high risk features including lymphovascular and perineural invasion were noted and 13/16 lymph nodes were positive for metastatic carcinoma. Two thirds of celiac lymph nodes were additionally positive for malignancy as well. Immunohistochemistry was positive for CK19, MOC31, CK7, CDX2, trypsin, chymotrypsin and BER-EP4.
Due to the patient’s poor response to neoadjuvant therapy, adjuvant modified FOLFIRINOX was started, and 6 cycles were given. Restaging CT of the chest/abdomen/pelvis showed new pulmonary nodules, mediastinal, hilar, mesenteric root and retroperitoneal adenopathy, all findings concerning metastatic disease. A new lesion in the right lobe of the liver was also discovered, measuring 1.2 cm. PET scan further showed hypermetabolic activity in the mediastinum, hilar regions, liver, and mesentery near the pancreas. NGS was notable for the BRAF V600E mutation. Tumor mutational burden (TMB) was 4.2 m/MB. No microsatellite instability was present. PD-L1 was expressed with a tumor proportion score (TPS) of 2%. Combined positive score was 5%. Due to the patient’s BRAF V600E mutation, she was started on dabrafenib 150 mg twice a day and trametinib 2 mg daily. Repeat PET-CT after four months of treatment showed interval resolution of metastatic hypermetabolic uptake as seen in Figure 2. PET-CT continued to maintain complete resolution of hypermetabolic uptake after 7 months of treatment. CA 19-9 notably decreased to 10 U/ml, within normal limits.
PET-CT scan of Patient 1, after receiving 4 months of targeted therapy with notable resolution of hypermetabolic disease in the liver and mesentery, indicating response to targeted therapy.
Patient 2. An 81-year-old male with a past medical history of hypertension, type 2 diabetes mellitus, and hypothyroidism initially presented with complaints of abdominal pain, unintentional weight loss and jaundice. Initial workup was significant for total bilirubin 8.0 mg/dl. CA 19-9 was 212 U/ml.
CT of the abdomen and pelvis showed intrahepatic and extrahepatic ductal dilation and a soft tissue fullness/mass-like structure in the pancreatic head measuring 2.6 cm as shown in Figure 3. CT of the chest showed no metastatic disease. Subsequent EUS/ERCP confirmed the findings of the mass in the pancreatic head. A plastic biliary stent was placed for a malignant biliary stricture. Fine needle biopsy of the pancreatic tissue was significant for atypical ductal cells. Due to the resectable nature of the pancreatic mass with no vascular involvement or metastatic disease, the Whipple procedure was performed. Pathology showed invasive poorly differentiated ductal adenocarcinoma with focal signet cell features. Surgical margins were negative for malignancy. High risk features including perineural invasion and lymphovascular invasion were present. Two out of 23 lymph nodes were positive for the tumor.
Initial scans of Patient 2, showing a disease burden with a mass-like structure in the pancreatic head measuring 2.6 cm.
The patient thereafter completed 6 cycles of adjuvant gemcitabine and capecitabine. He remained disease-free until three years later, when repeat staging scans showed soft tissue extension along the superior mesenteric artery and stenosis of the splenic vein and inferior mesenteric vein, concerning for local recurrence. Repeat EUS showed an irregular mass in the peripancreatic region, measuring 2.3 cm. Fine needle biopsy was positive for adenocarcinoma. The patient subsequently completed 8 cycles of mFOLFIRINOX with stable disease on imaging and significant decrease in CA 19-9 to 8 U/l. This was followed by capecitabine and radiation therapy (180 Gray administered over 5 fractions) to the pancreas. The patient remained on maintenance capecitabine for 5 months. However, small volume ascites and a peritoneal nodule was noted on repeat staging CT of the chest, abdomen, and pelvis. Diagnostic laparoscopy and biopsy of the peritoneal nodule confirmed a diagnosis of metastatic adenocarcinoma. He restarted mFOLFIRINOX once again and completed 6 cycles with a CA19-9 response to 21 U/l (down from 300 U/l). Repeat staging showed no local recurrence or distant metastasis. The patient had NGS performed on the tumor specimen that revealed BRAF V600E, PIK3CA E545K, and MUTYH G382D mutations. No microsatellite instability was present. TMB was 4 m/MB, PD-1 expression was 0%. Due to the presence of a BRAF V600E mutation, he was initiated on dabrafenib and trametinib. At 6 months and 9 months of targeted therapy, repeat staging scans showed a stable disease as shown in Figure 4. CA 19-9 remained within normal limits.
CT scan of Patient 2 after 6 months of targeted therapy indicating stable disease with no new metastases.
Patient consent. Verbal consent was obtained from patients described in this case report.
Discussion
Pancreatic adenocarcinoma is diagnosed late in the course of the disease and traditionally portends a poor prognosis despite surgical resection and adjuvant chemotherapy. Genomic sequencing has become more frequently used as it can help guide therapy. We present two cases of pancreatic adenocarcinoma refractory to mFOLFIRINOX that had genomic sequencing positive for the BRAF V600E mutation. Each case was significant for at least a partial response to dabrafenib and trametinib, a BRAF and MEK inhibitor respectively, and both patients are still being monitored for further response and signs of drug resistance.
BRAF V600E mutations are a component of the MAPK/ERK pathway leading to activation of growth factors that culminate in cell growth and survival (8). These mutations are present in approximately 50% of melanomas and have been successfully treated with BRAF inhibitors (BRAFi), such as vemurafenib and dabrafenib, and MEK inhibitors, such as trametinib and cobimetinib (9). However, BRAF V600E mutations in non-melanoma cancers, such as pancreatic cancer, are typically associated with aggressive disease resulting in decreased overall survival (OS) and progression free survival (PFS) (9). Research on BRAF alterations has shown that the BRAF V600E mutation is mutually exclusive with KRAS mutations; 30% of KRAS wild-type PDAC patients have BRAF mutations (7, 10). There is a significant inverse correlation between the two mutations, which results in differences in treatment response (7, 10). However, research on BRAFi in BRAF mutated pancreatic adenocarcinoma is limited due to rarity of the disease; 3% of advanced pancreatic adenocarcinoma cases are BRAF V600E positive (5, 7). A literature review on the use of BRAFi in pancreatic cancer is limited primarily to case reports or discussed in the context of all non-melanoma cancers. Below, we summarize a literature review which includes several cases of advanced pancreatic cancer with progression on mFOLFIRINOX and/or gemcitabine nab-paclitaxel, and the subsequent improvement on BRAFi therapy.
Hyman et al. analyzed patients with BRAF V600 mutations in non-melanoma cancers (n=122); however, out of the patient population, only one patient had PDAC (9). The response rate was 50% in all patients, including the PDAC patient, with one patient attaining a complete response, and sixteen attaining partial response after treatment with vemurafenib. This study emphasized the benefit of targeted therapy in non-melanoma cancers with improvement, contributing a basis for BRAFi use in PDAC (9).
Several case reports discuss targeted therapy based on genomic sequencing in PDAC (Table I). Patients discussed had metastatic pancreatic cancer and were on FOLFIRINOX or gemcitabine and nab-paclitaxel with disease progression (6, 7, 11-17). They subsequently underwent genomic sequencing and were found to have BRAF mutations, mainly V600E, though some cases demonstrated a deletion of BRAF or a second mutation. KRAS wild-type and BRAF V600E positive metastatic pancreatic cancers demonstrated at least a partial response to BRAF/MEK inhibitors (6, 7, 12-13, 15-17). Ardalan et al. reported that cobimetinib plus gemcitabine and paclitaxel resulted in a complete response to therapy after 16 months (16). Wang et al. reported a patient with stage IV metastatic PDAC and progression who had a partial response to vemurafenib and trametinib with a progression free survival of 17 months (17). Progression free survival in the KRAS wild-type and BRAF V600E case reports ranged widely from approximately 4 to 17 months (6, 7, 12-13, 15-17). Concomitant BRAF and P53 mutations were also observed and initially demonstrated partial responses to BRAF/MEK inhibitors before ultimately regressing (11, 14-15). Progression free survival in the case reports for BRAF and P53 mutations had a mean of 7 months with less variation than with KRAS wild-type, BRAF V600E (11, 14-15).
Brief literature review.
In summary, these case reports demonstrate partial to complete response on BRAF/MEK inhibitors in pancreatic cancer. Unfortunately, these responses were limited with several cases demonstrating disease relapse on targeted therapy. Given the small number of cases, however, it is difficult to make any definitive conclusions. Given the aggressive nature and poor 5-year survival rates, as noted prior, even partial responses to treatment extended progression free survival, reinforcing the utility of early genomic sequencing. However, PDAC sensitive to MEK inhibitors but resistant to BRAF inhibitors remains a possibility. Notable development of drug-resistance during ongoing treatment has been mentioned in the literature. Aguirre et al. presented a case of MAP2K2 resistance mutations that developed on trametinib for BRAF positive PDAC, which resulted in disease progression (11). Hong-Shuai et al. demonstrated a positive outcome with re-challenge therapy in the setting of BRAF V600E (6). In particular, initial BRAF/MEK inhibitor therapy with dabrafenib and trametinib resulted in serological and radiological improvement, for 12 months before regression; however, the patient responded to second-line BRAF/MEK inhibitor therapy with vemurafenib and cobimetinib with progression free survival for an additional 6 months, resulting in a survival time of more than 20 months since the initial diagnosis (6).
Conclusion
In conclusion, genomic sequencing should be considered early in disease diagnosis, especially if initial chemotherapy does not produce a response. BRAF mutations correlate with aggressive disease and poor chemotherapy response. BRAF positive pancreatic cancer should be identified early after diagnosis of cancer with therapy adjusted to target the specific mutation. In cases of disease progression, re-challenge therapy with second-line BRAF/MEK inhibitors can also be considered. We present two cases of BRAF positive pancreatic cancer treated with BRAF/MEK inhibitors with hopes of contributing to the growing discussion of targeted therapy in advanced pancreatic adenocarcinoma.
Footnotes
Conflicts of Interest
The Authors of this manuscript declare that they have no financial or non-financial conflicts of interest to disclose at this time with respect to this case report.
Authors’ Contributions
Shivani Shah: Writing of the original manuscript; editing/reviewing of the manuscript. Tabeer Rana: Writing of the original manuscript. Pragnan Kancharla: Conceptualization, editing/reviewing of the manuscript. Dulabh Monga: Conceptualization, editing/reviewing of manuscript.
- Received April 1, 2023.
- Revision received May 14, 2023.
- Accepted May 15, 2023.
- Copyright © 2023 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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