Pancreatic Ductal Adenocarcinoma with Atypical Genomic Profile: A Case of Long-Term Survival with KRAS-Wildtype, Microsatellite Instability and High Tumor Mutational Burden

Abstract

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, typically associated with late-stage diagnosis and limited survival despite advances in systemic therapy. Long-term survival in metastatic PDAC is exceedingly rare, and treatment strategies are limited by the intrinsic resistance of the tumor to standard therapies. However, emerging evidence suggests that molecular subtypes may exhibit distinct biological behaviors and may be amenable to new therapeutic options.

Case Presentation

We report the remarkable long-term survival of a 43-year-old male with a blank medical history, diagnosed with metastatic PDAC in 2018. The patient presented with postprandial upper abdominal discomfort that progressed to obstructive jaundice, leading to the discovery of a pancreatic head mass with metastatic lymphadenopathy. Despite the poor prognosis typically associated with metastatic PDAC, the patient achieved significant disease control through FOLFIRINOX chemotherapy and underwent surgical resection following complications from vascular involvement. Next-generation sequencing (NGS) revealed a rare KRAS-wildtype tumor with microsatellite instability (MSI) and a high tumor mutational burden (TMB). Moreover, a long-standing suspicion of Lynch syndrome could finally be confirmed.

Conclusion

This case highlights the potential impact of personalized treatment and molecular tumor profiling in reshaping the outlook for PDAC patients.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with an overall 5-year survival rate of approximately 13% [1]. This prognosis is even worse for metastatic PDAC [2]. Despite advancements over the years, effective treatments for metastatic pancreatic cancer remain limited. Chemotherapy regimens, such as FOLFIRINOX or gemcitabine with nab-paclitaxel, provide only a modest survival benefit [3, 4]. However, subsets of patients with distinct molecular characteristics, such as microsatellite instability (MSI) and high tumor mutational burden (TMB), may exhibit a more favorable response to chemotherapy or immunotherapy, challenging conventional prognostic assumptions.

Here, we present the case of a 43-year-old male with metastatic PDAC, characterized by a KRAS-wildtype profile, high TMB, and MSI, who achieved exceptional long-term survival following a combination of systemic chemotherapy and surgical resection. This case underscores the importance of a personalized, multidisciplinary approach in managing selected patients with advanced PDAC. Further studies are warranted to explore the role of a KRAS-wildtype profile, high TMB, and MSI in predicting outcomes and guiding treatment strategies in patients with PDAC.

We present the following case in accordance with the CARE reporting checklist. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000552404).

Case Presentation

Clinical History

The patient, a 43-year-old male with a blank medical history, initially presented in March 2018 with postprandial upper abdominal discomfort unresponsive to proton pump inhibitors. Testing for Helicobacter pylori was negative. By April 2018, he developed jaundice and dark urine, prompting further investigation. Figure 1 shows the timeline of the clinical course from symptom onset to the most recent follow-up, including investigations, outcomes, and treatments.

Fig. 1.

Timeline of clinical course. AFP, alkaline phosphatase; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; FNA, fine-needle aspiration; H&E, hematoxylin and eosin staining; KRAS-WT, KRAS-wildtype; MSI, microsatellite instability; PDAC, pancreatic ductal adenocarcinoma; TMB, tumor mutational burden; γGT, gamma-glutamyl transferase.

Family History

The patient’s family history was notable for multiple malignancies, including colon cancer in his mother at age 47 and brother at age 33, and uterine cancer in his mother at age 50. The family was suspected of Lynch syndrome for several years since immunohistochemical staining performed on a relative’s tumor at another medical center lacked MSH2 and MSH6 staining, but no germline mutation in MSH2 (or MSH6) had been found. Considering previous germline tests for hereditary causes of tumors occurring in the family were negative, genetic tests were not initially repeated in this patient.

Diagnostic Workup

Laboratory investigation in a peripheral medical center revealed an elevated bilirubin level of 5.96 mg/dL (upper limit of normal is 1.2 mg/dL). A 3-phase computed tomography scan (CT scan) identified a pancreatic head mass causing biliary obstruction, lymphadenopathy, and vascular encasement (online suppl. Fig. S1).

Endoscopic retrograde cholangiopancreatography (ERCP) confirmed malignant stenosis, and brush cytology was suggestive of malignancy. Following recovery from post-ERCP pancreatitis, a second opinion at our academic hospital led to the identification of a pathological left supraclavicular lymph node (online suppl. Fig. S2) in addition to the existing suspected malignant abnormality in the pancreatic head. Fine-needle aspiration of the supraclavicular lymph node revealed cytological features consistent with metastatic non-small cell carcinoma, which are shown at full resolution in online supplementary Figure S3.

Treatment Initiation

Palliative chemotherapy with FOLFIRINOX was initiated in May 2018. The patient tolerated the treatment well, with a 25% dose reduction over the course.

Treatment Response and Progression

After 16 cycles, imaging in February 2019 revealed significant regression of the pancreatic head mass, together with resolution of lymphadenopathy (online suppl. Figs. S4, S5), after which FOLFIRINOX was continued. However, a follow-up CT scan after 18 cycles in April 2019, identified an increased size of the pancreatic head tumor compared to the previous CT scan, but no liver metastases or locoregional lymphadenopathy. Considering both radiologic and clinical resolution of the supraclavicular lymph node, no additional locoregional therapy was provided.

Complications and Surgery

The patient experienced acute gastrointestinal bleeding in May 2019, due to a pseudoaneurysm of the aberrant right hepatic artery, which was managed with embolization. Recurrent bleeding 2 days later prompted coiling of the gastroduodenal artery. Given the patient’s age, good clinical condition, and initial response to chemotherapy, as well as high rebleeding risk, a pancreatoduodenectomy (Whipple procedure) was performed 3 days later, alongside a necrosectomy of the mesocolon.

Histopathological examination revealed a poorly differentiated PDAC with peri/intra-neural invasion and lymph node metastases (2/11) with an extension of the tumor into the vascular groove and the posterior dissection plane, staged as ypT3N1 (R1). The pathological response to the previous FOLFIRINOX chemotherapy was assessed as partial regression, with 60% of neoplastic cells remaining (Evans grade IIa). Pictures of immunohistochemical staining are included in the timeline in Figure 1 and can be viewed in full resolution in online supplementary Figures S6–S9. Noticeably, MLH1/PMS showed no loss of core expression, but in MSH1/6, only occasionally a weak positive core was observed, rendering loss of expression uncertain. The case was discussed in the multidisciplinary oncological board meeting. It was decided not to treat with adjuvant chemotherapy because 16 cycles of FOLFIRINOX were recently administered.

Molecular Tumor Profiling

Given the patient’s age, molecular analysis was conducted as part of the PAN-NGS trial (DTR NL75415, MEC-2020-0913) [5]. This nationwide prospective cohort study included young patients (≤60 years) with pathologically confirmed PDAC at all disease stages, regardless of treatment status. Tumor DNA and RNA were isolated from representative, formalin-fixed paraffin-embedded (FFPE) tumor samples, on which whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) were performed. Reports were reviewed and discussed monthly in a Molecular Tumor Board (MTB) composed of oncological surgeons, medical oncologists, researchers, pathologists, clinical molecular biologists in pathology, and clinical geneticists, all specialized in PDAC. These results highlighted a KRAS-wildtype tumor with MSI and high TMB (35 mutations/megabase). Additional immunohistochemical (IHC) staining showed loss of MSH2 and MSH6 core expression, and normal core expression of MLH1 and PMS2. Besides KRAS, two of the other most mutated genes in PDAC were also not detected in this patient, namely, TP53 and SMAD4. A likely pathogenic variant in CDKN2A was identified. Another potentially actionable mutation detected was a pathogenic PIK3CA variant. MSI status by next-generation sequencing (NGS) was determined by direct analysis of known microsatellite regions sequenced on the Caris Molecular Intelligence NGS panel. TMB analysis was performed based on NGS analysis from genomic DNA isolated from FFPE tumor samples using the Illumina platform, both of which have previously been described [5]. Additional pathological investigations also confirmed elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) in the tumor.

Clinical Genetics

Based on the family's oncological history, the MSI from the NGS, and loss of nuclear MSH2/MSH6 expression in the tumor, the MTB advised referring the patient to the clinical geneticist for revision. Recently, a cryptic MSH2 germline-splice site mutation (LLP004) was detected in the family at the Department of Human Genetics at the Radboud Medical Center, Nijmegen [6]. This enabled genetic testing of the patient and confirmed the carrier status for the familial pathogenic germline MSH2 mutation.

Follow-Up

The patient underwent biannual follow-up, including CT scans, tumor marker evaluation (carcinoembryonic antigen [CEA] and carbohydrate antigen 19-9 [CA 19-9]), and colonoscopies as part of Lynch syndrome screening. As of January 2025, nearly 7 years after diagnosis, the patient remains in excellent condition, with no evidence of disease recurrence.

Discussion

This case illustrates an exceptional outcome in metastatic pancreatic ductal adenocarcinoma, challenging the typically dismal prognosis associated with this disease. The patient’s long-term survival can likely be attributed to systemic chemotherapy, surgical resection, and a unique molecular tumor profile, including MSI and high TMB, along with the absence of a KRAS mutation. PDAC patients with tumors harboring a TMB-high profile and KRAS-WT are more often found to be long-term survivors [7–9], potentially due to an increased immune response in the tumor. In TMB-high tumors, T-helper cells and dendritic cells are elevated, priming cytotoxic T cells [7]. Moreover, additional neoantigens can serve as targets for the immune system and immunotherapy, especially in tumors that are also MSI [10]. The combination of high numbers of neoantigens and the most abundant CD8+ T-cell infiltrates is associated with long-term survival [11]. The microenvironment of KRAS-WT tumors also shows enhanced infiltration of cells associated with anti-tumor responses, such as CD8+ T cells, natural killer cells, and myeloid dendritic cells [8]. Simultaneously, MSI and high TMB occur more often in KRAS-WT tumors [8]. While MSI is uncommon in PDAC, it has been associated with improved survival, and patients with PDAC in the context of Lynch syndrome exhibit improved survival compared to sporadic cases [12, 13]. A favorable response to immunotherapy has been described [14, 15], but MSI status alone does not guarantee a response; however, the combination of MSI and TMB-high status improves these chances [16, 17]. Nevertheless, pembrolizumab is FDA-approved for advanced PDAC with MSI following progression on prior treatment [18]. Additionally, EMAST positivity in the tumor may enhance the efficacy of immunotherapy in this case, although this has not yet been proven in PDAC [19, 20].

Although high TMB is rare in PDAC with a 1–2% prevalence [17, 21], this mutational profile may occur more often in younger PDAC patients [5, 22, 23], potentially serving as a helpful indicator in the diagnostic process. Moreover, studies of targetable mutations in PDAC also show that a high TMB profile is often accompanied by other potentially actionable mutations, as in KRAS-WT tumors [5, 7–9]. In this case, features like MSI and a pathogenic missense mutation in PIK3CA highlight the value of comprehensive molecular testing in the presence of KRAS-WT and high TMB profiles. The absence of KRAS mutations further distinguishes this case as nearly 90% of PDAC cases harbor KRAS mutations associated with resistance to therapy [24].

Current literature does not support the long-term response to FOLFIRINOX observed in this case [24]. To date, only one study on metastatic pancreatic cancer patients has demonstrated improved outcomes with FOLFIRINOX treatment in individuals with deficient mismatch repair systems (associated with MSI status) compared to those with intact mismatch repair systems [25]. However, improved progression-free survival has been observed in KRAS-WT tumors previously [9], which could also account for this patient’s good response and prolonged disease-free survival.

Moreover, in this specific case, surgery was performed because of multiple factors: age, clinical condition, chemotherapy response, and rebleeding risk. Generally, patients with metastatic PDAC are not considered for surgical resection as the disseminated nature of the disease leads to continued progression. This means the surgery does not lead to life extension, while serious complications may occur. However, successful cases of (oligo)metastatic PDAC have previously been reported to result in increased life expectancy. To achieve this, it is extremely important to select patients with metastasis suitable for surgery, which can be based on various factors, such as the amount and location of metastasis, response to and duration of chemotherapy, CA19-9 levels and reduction, location of the primary tumor, duration of progression-free survival, molecular profiling/subtyping, and performance status [26–29]. Our case presented with one metastasis, in the supraclavicular region rather than the liver, with a 1-year progression-free survival and an initial good response to FOLFIRINOX chemotherapy over 10 months, greatly reducing the primary tumor and even dissolving the single metastasis. The course of CA19-9 levels is unknown, unfortunately, as the chemotherapy was provided at another hospital, and these levels were not measured. The first CA19-9 measurement at our center in January 2019 was 32 kU/L, and at the time of progression, 47 kU/L.

Molecular profiling of pancreatic tumors may hold relevant treatment information; however, acquiring sufficient tissue for comprehensive molecular analysis remains challenging [5]. The high stroma component often leaves primary tumor biopsies with tumor cell percentages or tumor tissue surface area too low for reliable results [5, 30]. However, specific KRAS testing has reduced tissue requirements [31], and MSI can be tested with IHC, requiring only a small number of FFPE slides.

This case underscores the value of molecular tumor profiling in guiding personalized treatment strategies, particularly in patients with atypical presentations or unexpected responses to standard therapies. Additionally, malignancies in the patient’s personal and family history should be inquired about as this may indicate a hereditary predisposition with specific mutation patterns for which specific treatment options may be available. Especially in this case, the patient’s family had been previously tested without confirming heredity. Nevertheless, it is important to assess each case individually and conduct additional research when indicated. This can yield valuable insights for both patients and (healthy) germline carriers, particularly when previous tests were performed some time ago. The ongoing advances in molecular knowledge and techniques ultimately enabled the confirmation of Lynch syndrome in this patient [6, 32]. Earlier diagnosis of Lynch syndrome and the underlying genetic landscape of the tumor could have altered the treatment decisions and potentially the subsequent clinical course in this case. Multiple courses of FOLFIRINOX (n = 16) were administered due to a strong disease response, and it was well tolerated. The standard of care for metastatic PDAC is 12 courses. Eventually, the patient experienced polyneuropathy grade II and fatigue, and thrombocytes were decreasing (96 × 10⁹/L). Tumor progression was visualized, and ultimately, a Whipple procedure was performed because of tumor bleeding. An earlier diagnosis of the genetic landscape of the tumor of this patient would have justified earlier treatment with immune checkpoint inhibitors [33]. FOLFIRINOX-related side effects may have been prevented or less pronounced, and surgery may not have been necessary. However, it remains uncertain how the clinical course would have evolved in this case with a different approach, including whether the patient would have remained free of disease or progression.

This case report has some limitations that must be acknowledged. As this patient remains disease-free, no statement can be made regarding a possible immunotherapy response. Also, as both KRAS-WT and MSI and TMB-high are rare in this patient’s tumor, it is hard to determine which condition leads to the good response to chemotherapy and long-term survival, or whether this can be attributed to the combination of these factors. However, the extensive NGS performed, including WTS and WES, provides insight into all potentially contributing factors. In addition, this increases the treatment options for our patient, in case of disease recurrence.

Conclusion

This report highlights the importance of a multidisciplinary approach and the potential of (detailed) molecular profiling in managing pancreatic ductal adenocarcinoma. This patient's exceptional 7-year survival demonstrates that aggressive multimodal therapy, informed by molecular insights, can significantly alter the prognosis of metastatic PDAC in selected cases. Moreover, it is of utmost importance to conduct genetic testing based on clinical indication, regardless of previous results, as new tests can reveal unexpected findings and alter prognosis and treatment options.

Acknowledgment

The authors would like to give special thanks to the patient whose case report is concerned.

Statement of Ethics

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Ethical approval is not required for this study under local guidelines. All procedures performed in this study were in accordance with the ethical standards of the Institutional and/or National Research Committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Conflict of Interest Statement

All authors have completed the ICMJE uniform disclosure form. The authors have no conflicts of interest to declare.

Funding Sources

This work was supported by Merus. Merus NV had no further role in study design, data collection, analysis, interpretation, or manuscript writing.

Author Contributions

Conception and design, collection and assembly of data, and administrative support: G.J.S. and C.H.J.E. Provision of study materials or patients, data analysis and interpretation, manuscript writing, and final approval of manuscript: G.J.S., M.C.D., B.L., A.W., J.W.W., and C.H.J.E.

Funding Statement

This work was supported by Merus. Merus NV had no further role in study design, data collection, analysis, interpretation, or manuscript writing.

Data Availability Statement

The data supporting the findings of this study are not publicly available because they contain information that could compromise the privacy of the patient but are available from C.H.J.E. upon reasonable request.