Brain metastasis from KRAS wild-type pancreatic cancer and organoid correlates: a case report

Introduction

Pancreatic cancer is widely regarded as one of the most aggressive and deadly cancers, currently ranked as the third leading cause of cancer-related deaths in the United States (1). The most prevalent subtype, pancreatic ductal adenocarcinoma (PDAC), accounts for over 85% of pancreatic cancer cases and is still challenging to treat, often showing resistance to conventional therapies (2). Although surgery is considered its only potential cure, PDAC is often inoperable when found in patients due to the lack of symptoms or diagnostic tools to identify early disease, as well as its invasive nature (3,4). PDAC is thus usually diagnosed as advanced or metastatic disease in up to 80% of cases (3). Its most common metastatic sites include the liver (76–80%), peritoneum (48%), and lungs (45%) (5,6). Brain metastases (BrMs) are an exceptionally rare complication, with an estimated incidence of less than 1% (7,8). This is likely due to the rapid progression of pancreatic cancer where patients often die before developing or showing symptoms of brain disease (9). Furthermore, brain imaging is not recommended in the initial diagnosis and follow-up routine assessments of asymptomatic pancreatic cancer as per the National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines. As efforts to cure pancreatic cancer progress and survival rates improve, previously rare metastases may become more common, underscoring the importance of studying and understanding whether particular molecular drivers may induce unusual tropism, as such findings could be targets for personalized medicine (10).

Patient-derived organoids (PDOs) are three-dimensional cell culture models highly valued in cancer research because they retain key molecular characteristics and the heterogeneity of the original tumor, providing a valuable framework for testing drug responsiveness and resistance specific to an individual’s cancer (11,12). The aims of this case report are to describe a clinically significant case of BrM in a patient with PDAC, highlight the importance of sequencing and precision medicine to characterize rare and aggressive cancers, and demonstrate the potential of PDOs in exploring interesting, targeted therapies. We present this article in accordance with the CARE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-818/rc).

Case presentation

Clinical case presentation

A 69-year-old male with a history of smoking (40 pack-years), presented to Memorial Sloan Kettering in May 2022 with complaints of back and abdominal pain, early satiety, and unexplained weight loss (Figure 1A,1B). He was previously diagnosed with chronic pancreatitis and prescribed pancreatic enzymes and a proton pump inhibitor, both of which had negligible effect on his symptoms. Computed tomography (CT) imaging of the chest, abdomen, and pelvis showed coarse calcifications in the pancreatic head and uncinate process, as well as extensive retroperitoneal adenopathy surrounding the pancreas and major arteries (Figure 1C,1D). The patient underwent a diagnostic biopsy of the retroperitoneal lymph node in June 2022, part of which was sent for PDO establishment, though this first attempt was unsuccessful (Appendix 1). Pathological assessment and immunohistochemical staining of the biopsy revealed poorly differentiated carcinoma with focal CDX2 expression; CK7, CK20, TTF1, trypsin, chymotrypsin, and NKX3.1 were negative and expression of SMAD4 was retained. Hematoxylin and eosin (H&E) staining confirmed adenocarcinoma with well-formed glandular structures lined by tumor cells containing intracytoplasmic mucin, which excluded testicular cancer, lymphoma or infection, which can also present with retroperitoneal adenopathy. TTF-1 and NKX3.1 negativity made a lung or prostate primary unlikely. Pancreatobiliary carcinomas lack a definitive site-specific immunohistochemical marker, however, given the characteristic morphology and exclusion of the most common histologic mimickers by immunohistochemistry, we were confident that the findings are most consistent with a pancreatic primary. Next generation sequencing of circulating tumor DNA (ctDNA) showed somatic mutations in TSC2 and PDGFRβ, amplifications in MYC, ERBB3, and MDM2 as well as rearrangement in STK11, among others. No KRAS or TP53 mutations were found (Tables 1,2). Upon these findings, the patient was diagnosed with metastatic pancreatic ductal adenocarcinoma (PDAC). He was enrolled in the Pancreatic adenocarcinoma signature stratification for treatment-01 (PASS-01) clinical trial (NCT04469556) and randomized to the gemcitabine nab-paclitaxel (GnP) arm of the study. He received six months of treatment, followed by four months of maintenance therapy with monotherapy gemcitabine after developing progressive neuropathy, a common adverse effect of nab-paclitaxel (13) (Figure 1A,1B).

Figure 1 Patient disease timeline and primary tumor imaging. (A) Case report timeline. (B) Patient’s CA19.9 levels. (C,D) Baseline CT imaging, cystic lesion in the uncinate process of the pancreas (C) and left para-aortic adenopathy (D). BrM, brain metastasis; CA19.9, carbohydrate antigen 19-9; CNS, central nervous system; CT, computed tomography; Gem, gemcitabine; GnP, gemcitabine nab-paclitaxel; PDO, patient-derived organoid; RP LN, retroperitoneal lymph node.

Ten months after the first PDAC diagnosis, in April 2023, the patient presented with dizziness. Magnetic resonance imaging (MRI) of the brain showed lesions consistent with bilateral supra- and infratentorial BrMs, including a 4.6 cm × 2.7 cm mass in the left cerebellum (Figure 2A), 0.9 cm foci in the right basal ganglia and 0.5 cm foci in the right anterior frontal lobe. The patient underwent a craniotomy to remove the left cerebellar mass, followed by whole-brain and targeted radiation therapy (RT). A part of the resected BrM was sent for PDO establishment, which was successful. Histologic and genomic assessment of the resected mass and sequencing of the metastasis and cerebrospinal fluid (CSF) ctDNA confirmed that the BrM was a PDAC metastasis, showing phenotypic similarities to the primary lesion and previously sequenced blood ctDNA (Figure 2B, Tables 1,2). In addition, this new round of sequencing revealed many copy number alterations such as a CCNE1 amplification, not previously picked up due to low cellularity. After the craniotomy and radiation, the patient was switched to nano-liposomal irinotecan (SN-38), 5-fluorouracil (5-FU), and leucovorin (NALIRIFOL) for three months due to disease progression before being consented to the MYTHIC clinical trial in August 2023 (NCT04855656), where he received RP-6306, a PKMYT1 inhibitor that has shown efficacy in CCNE1-amplified cancers (14). He remained on this treatment for 2 months.

Figure 2 Genomic and histologic overview of patient and CNS lesions imaging. (A) MRI imaging left cerebellum metastasis. (B) H&E staining of patient primary tumor, brain metastasis and PDO. Scale: black, 100 nm. (C) MRI imaging, enhancing nodule along the posterior cauda equina at L1–L2. The yellow arrows show tumor lesions. Figure 1A,1B were made using BioRender. BrM, brain metastasis; CNS, central nervous system; H&E, hematoxylin and eosin; LN, lymph node; MRI, magnetic resonance imaging; PDO, patient-derived organoid.

In November 2023, 6 months after the BrM diagnosis, new brain, and osseous spinal metastases, as well as leptomeningeal disease (cervical, thoracic, and lumbar spine) were detected on MRI (Figure 2C). At this time, the patient received 10 fractions of proton RT to the central nervous system (CNS) before being switched to a GnP regimen for one month as GnP had previously seemed to control his non-CNS disease. The patient developed progressive pain and weakness related to progression of his extracranial disease, while his BrM stabilized following RT. The patient then transitioned to hospice care and passed away in February 2024, 9 months after the BrM diagnosis and 21 months after the original diagnosis.

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 publication of this case report and accompany images. A copy of the written consent is available for review by the editorial office of this journal.

PDO presentation

Upon tissue receipt in April 2023, the BrM-derived PDO was cultured, biobanked, and sequenced (Figure 3A). Genomic sequencing results of the PDO aligned with the patient’s sequencing data, showing the same KRAS wild-type (WT) and TP53 WT statuses as the BrM (Tables 1,2). Histologic evaluation by a board-certified pathologist further confirmed the PDO as a high-grade carcinoma, phenotypically similar to the patient’s lymph node and BrM lesions (Figure 2B). Together, these findings confirmed the PDO as a faithful model of the patient’s cancer.

Figure 3 PDO drug screening and response. (A) PDO brightfield images at ×4 and ×20. Scale: black, 100 nm, yellow, 500 nm. (B) High content images of BrM PDO at ×10, stained with AOPI live/dead stain (green = live, red = dead). Staurosporine as positive control (dead), DMSO as negative control (live). (C) Violin plots of BrM PDO drug response, using AUC (red) compared to previously published PDO cohort (11) (black). 5-FU, 5-fluorouracil; AFA, afatinib; AOPI, acridine orange and propidium iodide; AUC, area under curve; BrM, brain metastasis; DMSO, dimethyl sulfoxide; GEM, gemcitabine; PAC, paclitaxel; PDO, patient-derived organoid; SN-38, active form of irinotecan; Stauro, staurosporine.

The PDO was screened against over 100 compounds, including standard-of-care (SOC) chemotherapies, targeted drugs, and investigational compounds (Figure 3B,3C). Comparison with a previously published organoid biobank (11) revealed that the PDO exhibited resistance to SOC treatments. The patient had received gemcitabine and paclitaxel until the development of the BrM from which the PDO was derived. Following BrM resection, SN-38 and 5-FU were administered but did not improve the patient’s condition as he continued to progress. In both cases, the PDO’s responses mirrored the patient’s clinical outcomes, underscoring its ability not only to replicate but also potentially predict therapeutic responses. Although the patient also received RP-6306, the compound was unavailable for research during the experimental design phase. This highlights a common challenge in research, where drugs in advanced clinical trials are still inaccessible, hindering new discoveries.

However, the PDO showed sensitivity to afatinib and everolimus (Figure 3B,3C). Afatinib, an ErbB family inhibitor targeting HER2 and EGFR, shows increased efficacy in KRAS WT cancers compared to KRAS-mutant cancers (15). Everolimus, a rapamycin derivative and mTOR inhibitor, is highly effective in TSC2-mutated cancers (16). Despite the patient’s TP53 WT status, the PDO exhibited resistance to Nutlin-3, a p53-MDM2 inhibitor, possibly due to MDM2 amplification leading to reduced sensitivity. Although the PDO was KRAS WT, its growth was inhibited by the pan-RAS inhibitor RMC-6236, suggesting that RAS signaling is still a key driver of malignant proliferation (Figure 3B). These findings illustrate how PDO-based precision medicine could help find potentially beneficial treatments for patients. In fact, for tumors with atypical profiles (e.g., KRAS WT, targetable amplifications), PDOs could offer a platform to empirically find therapies when clinical trial options are limited.

Unfortunately, by the time drug screening from the BrM PDO was completed, the patient was in hospice care, and the findings could not be incorporated into his treatment plan.

Discussion

BrMs from PDAC are exceptionally rare, with limited documented cases in the literature. While synchronous BrM rates are currently reported at less than 1%, an autopsy study revealed a 10% incidence of post-mortem BrM in pancreatic carcinoma patients (17). This discrepancy may stem from the fact that head imaging is not part of the standard diagnostic and follow-up workup for PDAC, suggesting that BrMs could be underdiagnosed and more prevalent than previously recognized. Notably, the advent of RAS inhibitors for KRAS-mutated cancers and other targeted therapies is expected to prolong PDAC patient survival, potentially increasing the likelihood of symptomatic BrMs and other unique metastatic presentations.

To our knowledge, the first ante-mortem diagnosed PDAC BrM cases were reported in South Korea in 2003. Our literature review found 28 cases from 2003 to 2023, with a median age at PDAC diagnosis of 59 years (range, 34–80 years) and a slight male predominance (64%) (Tables 3,4). Most patients received chemotherapy (82%), surgery (50%), or radiation (11%) for their primary disease, with a median time to BrM development of 11 months (range, 0–82 months). Common BrM treatments included radiation (68%), surgery (46%), and chemotherapy (25%), with a median overall survival of 6.5 months (range, 0–132 months). Synchronous metastases often involve the liver (32%), lungs (29%), lymph nodes (29%), and bones (2%), with one case presenting concurrent spinal cord metastasis (Table 4). In our report, a 69-year-old male developed BrM 10 months after PDAC diagnosis and underwent surgery, radiation, and chemotherapy.

This patient was enrolled in the PASS-01 trial, a phase II randomized study comparing GnP and modified FOLFIRINOX (mFFX) in metastatic PDAC. The trial incorporates multi-pass core biopsies for pathology, whole-genome/RNA sequencing, and PDO generation with pharmacotyping (13). This approach aims to personalize treatment based on genetic, transcriptional, and pharmacological profiles. Despite a median overall survival of 9.7 months for GnP-treated patients in PASS-01 (13), our patient survived 21 months—likely attributable to his unique KRAS/TP53/CDKN2A wild-type (WT) tumor, which harbored a CCNE1 amplification and qualified him for the MYTHIC trial. KRAS WT PDACs are associated with better prognoses and higher rates of actionable alterations (37), underscoring the importance of including genomic profiling in the clinical setting.

In our review, we observed only a few PDAC BrM reported cases having genomic data on the patients’ tumors. A study from 2018 in showed that mutations in KRAS, TP53 and MYC amplification were most common in their PDAC BrM cohort (38). In lung adenocarcinomas, MYC is also one of the most altered genes in BrMs, along with EGFR alterations (39). The patient in this case report however harbored both MYC and ERBB3 amplifications. ERBB3, or HER3, is a member of the EGFR family which has been identified in the majority of BrMs from breast and non-small cell lung cancers (40). Additionally, HER3 binds to neuregulin-1 (NRG1), a growth factor highly present in the brain as it is secreted by both microglia and neurons. In fact, Momeny et al. have shown that NRG1 and HER3 interact, along with HER2, and promote a blood-brain barrier trans-endothelial migration of human breast cancer cell lines (41). CCNE1 amplification was also enriched in the CSF of patients with gastric cancer and leptomeningeal metastases (42). Additionally, unlike the majority of published case reports, this patient’s BrM is poorly differentiated, lacking common epithelial markers like CK7. Together, these may be key factors explaining the brain tropism in this patient.

PDOs, generated through dissociation of tumor tissue into single cells, have demonstrated remarkable fidelity in recapitulating the genetic and transcriptional profiles of patient tumors (11). This makes them powerful models for drug sensitivity testing and precision medicine applications (12). While the PDO data in this particular case could not guide clinical decisions due to the extended establishment timeline, this technology holds significant promise for real-time therapeutic guidance in other patients and for expanding our understanding of individual tumor biology. Within the PASS-01 trial, successful PDO generation was achieved for 50% of patients, with an average turnaround time of approximately two months from tissue acquisition to drug screening results (43). Notably, a subset of cases yielded pharmacotyping data within just one month—a timeline that could meaningfully inform second-line therapy selection for many patients. In this report, the PDO identified patient sensitivity to therapies that may not have been routinely considered and demonstrated resistance to standard of care regimen, which the patient received and progressed on. This case exemplifies how integrating PDO-based pharmacotyping with comprehensive molecular profiling can identify novel treatment strategies for rare PDAC variants. The combined analysis of clinical, genomic, and functional model data thus establishes a valuable framework for investigating atypical cancer presentations and optimizing personalized therapeutic approaches.

Conclusions

This report presents a rare case of PDAC BrM alongside the successful generation and pharmacotyping of a PDO. Our findings emphasize the transformative potential of precision medicine in characterizing and treating rare PDAC manifestations through multidisciplinary approaches. Additionally, we propose that KRAS WT and ERBB3-amplified PDAC patients might be candidates for closer follow up, including routine brain imaging, and that PDO protocols be improved to be useful in rapidly progressing diseases.

Acknowledgments

We would like to thank the Organoid and Histology Shared Resources at Cold Spring Harbor Laboratory for their assistance in generating and processing the PDO. The authors would also like to thank the Lustgarten Foundation. We would like to thank the David M. Rubenstein Center for Pancreatic Cancer Research, the Bioinformatics Core, and Integrated Genomics Operations at Memorial Sloan Kettering Cancer Center for their help in sequencing the PDO and patient samples. A special acknowledgement goes to the Gail V. Coleman and Kenneth M. Bruntel Organoids for Personalized Therapy Grant. Organoid images were generated on the HCI, formally named “Ken” in honor of their donor support. We would also like to acknowledge the support of our fellow PDAC Brain Metastasis Consortium members including Antonio T. Baines, Howard C. Crawford, James Lee, Daniel A. King, Heena Kumra, Sonu Subudhi and Rakesh K. Jain. And finally, we extend our gratitude to the patient and their family who contributed to this study.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-818/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-818/prf

Funding: This work was supported by CSHL Cancer Center Core Funding and NCI grant (No. 5P30CA045508, to D.A.T.); MSK Cancer Center Funding (No. 5P30CA008748, to S.M. Vickers); the Lustgarten Foundation (Organoid Personalized Therapeutics Phase 3 and 4 Projects - OPT3 and OPT4); the Thompson Foundation (No. 5P30CA45508, to D.A.T. and P.A. Gilmoty); the Pershing Square Foundation, the Cold Spring Harbor Laboratory and Northwell Health Affiliation, the Northwell Health Tissue Donation Program, the Cold Spring Harbor Laboratory Association, and the National Institutes of Health (No. 5P30CA45508, to D.A.T. and P.A. Gilmoty; No. U01CA210240, to M.A. Hollingsworth and D.A.T.; No. R01CA229699, to C. Vakoc; No. U01CA224013, to D.A.T. and P. Robson; No. 1R01CA188134, to D.A.T. and No. 1R01CA190092 to D.A.T.). Additionally, this work was also supported by a gift from the Simons Foundation (No. 552716, to D.A.T.). This work was supported by a Postdoctoral Fellowship (No. PF-23-1036459-01-ET, to A.N.H.) (grant DOI #: 10.53354/ACS.PF-23-1036459-01-ET.pc.gr.168125), from the American Cancer Society.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-818/coif). D.A.T. is a member of the Scientific Advisory Board and receives stock options from Leap Therapeutics, Dunad Therapeutics, Xilis, and Mestag Therapeutics outside the submitted work. And D.A.T. is a scientific co-founder of Mestag Therapeutics. D.A.T. has received research grant support from Mestag, and ONO Therapeutics. These affiliations are not related to the work in this publication. Additionally, D.A.T. receives grant funding from the Lustgarten Foundation, the NIH, and the Thompson Foundation. K.Y. reports receiving research support from Ipsen, General Oncology, Onco C4, and AstraZeneca. The other authors have no conflicts of interest to declare.

Ethical Statement: 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. 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 publication of this case report and accompany images. A copy of the written consent is available for review by the editorial office.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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