This site is intended for US healthcare professionals only.

*Park, 2024: Phase 2, open-label, randomized study (n=585/2113) in patients with histologically confirmed mPC who were CLDN18.2 positive; Lyu, 2024: Retrospective analysis of CLDN18.2 IHC staining (n=309) in PDAC; Arseneau, 2024: Retrospective analysis of CLDN18.2 IHC staining (n=121) in PDAC.^2-4

^†Defined as ≥75% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining by IHC.^2-4

CLDN18=claudin 18; CLDN18.2=claudin 18.2; IHC=immunohistochemistry; mPC=metastatic pancreatic cancer; PDAC=pancreatic ductal adenocarcinoma.

Pancreatic cancer mortality is on the rise

Deaths from pancreatic cancer are expected to outpace most other cancers in the US. Pancreatic cancer is projected to be the second leading cause of cancer death by 2040.⁵

5-year survival rate for metastatic pancreatic cancer is 3.1% in the US.9

5-year survival rate for metastatic pancreatic cancer is 3.1% in the US.^11*

*SEER 22 (Excluding IL/MA) 2014-2020, All Races, Both Sexes by SEER Combined Summary Stage.

IL=Illinois; MA=Massachusetts; SEER=Surveillance, Epidemiology, and End Results.

Between 1997 and 2015, nearly 90% of Phase 3 clinical trials failed.8

Between 1997 and 2015, nearly 90% of Phase 3 clinical trials failed.¹² To date, there has been a low success rate for research in pancreatic cancer.^13-15

^†Based on a review of 30 randomized clinical trials in the first-line treatment of metastatic pancreatic cancer published from January 1997 to June 2015.¹²

Continued exploration into new and emerging biomarkers may uncover new insights into the complex nature of pancreatic cancer

Explore pancreatic cancer biomarkers

Consider testing for potential somatic mutations¹⁰

Fusions: ALK, NRG1, NTRK, ROS1, FGFR2, and RET

Microsatellite instability (MSI)

Mutations: BRAF, BRCA1/2, KRAS, and PALB2

Mismatch repair deficiency (dMMR)

Amplifications: HER2

Tumor mutational burden (TMB)

Select emerging biomarkers

that may help identify previously undefined subsets of patients:

CLDN18.2 is a component of tight junctions and has a role in the regulation of permeability, barrier function, polarity of epithelial layers, and controlling the flow of molecules between cells^16-18
KRAS G12C is a membrane-bound enzyme that signals cellular growth through the MAP and PI3K pathways¹⁹

Select established biomarkers

that are used to inform clinical decisions:

BRCA1 and BRCA2 genes are involved in the maintenance of genome stability²⁰
MSI/dMMR is characterized by the accumulation of mutations in microsatellite DNA sequences leading to genomic instability. MSI occurs when the DNA MMR is not functioning appropriately (mismatch repair deficiency; dMMR)²¹
NTRK genes encode transmembrane receptor tyrosine kinases that normally function to regulate the development, maintenance, and function of neural tissues²²

ALK=anaplastic lymphoma kinase; BRAF=v-raf murine sarcoma viral oncogene homolog B1; DNA=deoxyribonucleic acid; FGFR2=fibroblast growth factor receptor 2; HER2=human epidermal growth factor receptor 2; MAP=mitogen-activated protein; NRG1=neuregulin 1; PALB2=Partner And Localizer of BRCA2; PI3K=phosphoinositide 3-kinase; RET=REarranged during Transfection; ROS1=ROS proto-oncogene 1, receptor tyrosine.

CLDN18.2

CLDN18.2 is a novel biomarker detected at any level in ~60% of pancreatic tumors^1,23-25*
Approximately 1/3 of pancreatic tumors are CLDN18.2 positive^2-4†‡
- CLDN18.2 positivity is defined as ≥75% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining by IHC^2-4
CLDN18.2 positivity^‡ is putatively an independent positive predictor of survival in pancreatic cancer³
CLDN18.2 is not expressed in normal pancreatic tissue¹

*Wöll, 2014: Retrospective analysis of CLDN18.2 immunohistochemical staining (N=202) in primary pancreatic tumors; Zhang, 2022: Retrospective analysis of CLDN18.2 IHC staining (n=302) in PDAC; Tanaka, 2011: Retrospective analysis of CLDN18.2 IHC staining (n=224) in PDAC; Kayikcioglu, 2023: Retrospective analysis of CLDN18.2 IHC staining (N=68) in PDAC.^1,23-25

^†Park, 2024: Phase 2, open-label, randomized study (n=585/2113) in patients with histologically confirmed mPC who were CLDN18.2 positive; Lyu, 2024: Retrospective analysis of CLDN18.2 IHC staining (n=309) in PDAC; Arseneau, 2024: Retrospective analysis of CLDN18.2 IHC staining (n=121) in PDAC.^2-4

^‡Defined as ≥75% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining by IHC.^2-4

CLDN18=claudin 18; CLDN18.2=claudin 18.2; IHC=immunohistochemistry; mPC=metastatic pancreatic cancer; PDAC=pancreatic ductal adenocarcinoma.

CLDN18.2 in pancreatic cancer

CLDN18.2 expression has also been observed in esophageal adenocarcinoma, non-small cell lung cancer, ovarian mucinous adenocarcinoma, and gastric/gastroesophageal junction adenocarcinoma¹⁶

KRAS G12C

Despite KRAS G12C being an emerging biomarker in oncology, its mutation is relatively rare in pancreatic cancer¹⁹
KRAS G12C mutations can be detected via molecular testing (NGS)^10,27,28

KRAS G12C=Kirsten rat sarcoma viral oncogene homolog glycine 12 to cysteine; NGS=next-generation sequencing.

BRCA1 and BRCA2

BRCA1 and BRCA2 mutations are established biomarkers that are present in a variety of cancers³⁰
Mutations to BRCA genes (either inherited germline mutations or non-inherited somatic mutations) have been detected in pancreatic cancer^30,31
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pancreatic Adenocarcinoma recommend testing for BRCA via molecular profiling, preferably using an NGS assay¹⁰

BRCA1/2=BReast CAncer gene 1/2; NCCN=National Comprehensive Cancer Network®.

MSI/dMMR

MSI is an established biomarker that can be found in a broad range of solid tumor types²¹
Microsatellites are repeated sequences of nucleotides in DNA²¹
MSI occurs when the DNA MMR is not functioning appropriately (mismatch repair deficiency; dMMR)²¹
- This loss prevents normal repair and correction of DNA, allowing mismatches to occur²¹
- The MMR genes are the most frequently mutated genes in cancer²¹
Tumors with ≥30% expression of unstable microsatellites are referred to as MSI-high (MSI-H), while tumors with 10%-29% expression are considered MSI-low³⁴
NCCN Guidelines^® recommend testing for MSI/dMMR via molecular profiling, preferably using an NGS assay¹⁰
- IHC testing may also be used to detect dMMR³⁵

dMMR=deficient DNA mismatch repair; MMR=mismatch repair; MSI=microsatellite instability.

NTRK

NTRK fusions are established biomarkers that can drive malignant growth in several different cancers^10,37
Malignant NTRK fusions occur because of chromosomal rearrangements involving the NTRK 1, 2, and 3 genes³⁸
NCCN Guidelines recommend testing for NTRK via molecular profiling, preferably using an NGS assay¹⁰

NTRK=neurotrophic tyrosine receptor kinase.

Analysis of emerging and established biomarkers may provide a more targeted approach to the treatment of pancreatic cancer

As biomarkers emerge, it’s important to assess which testing methods are required³⁹

CLDN18.2 can be detected by IHC staining methods, a routine technique in pathology laboratories^3,35

IHC scoring for CLDN18.2 in pancreatic cancer is based on membrane staining intensity and the percentage of positive tumor cells¹
- CLDN18.1 is only present in the lungs. CLDN18.2 is the only CLDN18 isoform detected in the pancreas¹⁶
Healthcare professionals performing biopsies should acquire pancreatic tissue samples of sufficient size and quality for IHC testing⁴⁰

NGS can be used to detect many National Comprehensive Cancer Network^® (NCCN^®)-recommended biomarkers (MSI, BRCA1 & BRCA2, NTRK).¹⁰

KRAS G12C mutations can be detected via molecular testing (NGS).^27,28

Role of the pathologist

Close partnership with pathologists can optimize the use of available tissue for biomarker testing and decrease the need for additional biopsy⁴¹
Tissue quantity and quality matter. Preserving tissue architecture with endoscopic ultrasound-guided fine-needle biopsies, core needle biopsies, and resection yields samples with higher diagnostic sensitivity, allowing for more accurate IHC analysis^42-44

The prevalence of select emerging and established biomarkers varies

The prevalence of emerging and established biomarkers varies

Image is not reflective of specific biomarker locations in pancreas.

*Park, 2021 (KRAS G12C): A review of 24 randomized clinical trials, 4 meta-analyses, 3 systematic reviews, 5 guideline recommendations, and 37 observational and cohort studies in pancreatic cancer; Grant, 2015 (BRCA1/2): Retrospective analysis of BRCA1/2 expression (n=290) in patients with PDAC; Lowery, 2018 (BRCA1/2): Prospective analysis of BRCA1/2 expression (n=615) in patients with pancreatic exocrine cancers; Luchini, 2021 (MSI/dMMR): A systematic review of 34 studies that included 8323 patients with pancreatic cancer; Allen, 2023 (NTRK): Retrospective analysis of NTRK expression (N=400) in patients with PDAC.^{29,32,33,36,38}

CLDN18.2=claudin 18.2; IHC=immunohistochemistry; mPC=metastatic pancreatic cancer; PDAC=pancreatic ductal adenocarcinoma.

Continued investigations into emerging and established biomarkers can deepen our understanding of pancreatic cancer, provide greater insights into patient populations, and may help inform clinical decisions

References: 1. Wöll S, Schlitter AM, Dhaene K, et al. Int J Cancer. 2014,134(3);731-739. doi:10.1002/ijc.28400 2. Park W, O’Reilly EM, Li C-P, et al. Presented at: European Society for Medical Oncology (ESMO) Congress 2024; September 13-17, 2024; Barcelona, Spain. 3. Lyu SI, Fretter C, Simon AG, et al. Extent and clinical significance of the therapy-relevant tight junction protein claudin 18.2 in pancreatic ductal adenocarcinoma - real-world evidence [published online June 24, 2024]. Transl Oncol. 2024. Accessed October 18, 2024. https://www.sciencedirect.com/science/article/pii/S1936523324001712 4. Arseneau RJ, Kempster E, Bekkers C, et al. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy, 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res. 2024;12(10 Suppl):Abstract nr B028. 5. Rahib L, Wehner MR, Matrisian LM, Nead KT. Estimated projection of US cancer incidence and death to 2040 [published online April 7, 2021]. JAMA Netw Open. 2021. Accessed November 18, 2024. 6. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: common cancer sites. Accessed April 26, 2024. https://seer.cancer.gov/statfacts/html/common.html 7. Von Hoff DD, Ervin T, Arena FP, et al. N Engl J Med. 2013;369:1691-1703. doi:10.1056/NEJMoa1304369 8. Conroy T, Desseigne F, Ychou M, et al. N Engl J Med. 2011;364(19):1817-1825. doi:10.1056/NEJMoa1011923 9. Wainberg ZA, Bekaii-Saab T, Boland PM, et al. Eur J Cancer. 2021;151:14-24. doi:10.1016/j.ejca.2021.03.028 10. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Pancreatic Adenocarcinoma V.1.2025. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed December 31, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 11. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: pancreatic cancer. Accessed October 4, 2024. https://seer.cancer.gov/statfacts/html/pancreas.html 12. Thota R, Maitra A, Berlin JD. Preclinical rationale for the phase III trials in metastatic pancreatic cancer: is wishful thinking clouding successful drug development for pancreatic cancer? Pancreas. 2017;46(2):143-150. doi:10.1097/MPA.0000000000000753 13. DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ. 2016;47:20-33. doi:10.1016/j.jhealeco.2016.01.012 14. Katayama ES, Hue JJ, Bajor DL, et al. A comprehensive analysis of clinical trials in pancreatic cancer: what is coming down the pike? Oncotarget. 2020;11(38):3489-3501. doi:10.18632/oncotarget.27727 15. Wong CH, Siah KW, Lo AW. Estimation of clinical trial success rates and related parameters. Biostatistics. 2019;20(2):273-286. Erratum in: Biostatistics. 2019;20(2):366. doi:10.1093/biostatistics/kxx069 16. Sahin U, Koslowski M, Dhaene K, et al. Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development. Clin Cancer Res. 2008;14(23):7624-7634. doi:10.1158/1078-0432.CCR-08-1547 17. Tsukita S, Tanaka H, Tamura A. The claudins: from tight junctions to biological systems. Trends Biochem Sci. 2019;44(2):141-152. doi:10.1016/j.tibs.2018.09.008 18. Hu YJ, Wang YD, Tan FQ, Yang WX. Regulation of paracellular permeability: factors and mechanisms. Mol Biol Rep. 2013;40(11):6123-6142. doi:10.1007/s11033-013-2724-y 19. Wood LD, Canto MI, Jaffee EM, Simeone DM. Pancreatic cancer: pathogenesis, screening, diagnosis, and treatment. Gastroenterology. 2022;163(2):386-402.e1. doi:10.1053/j.gastro.2022.03.056 20. Stoppa-Lyonnet D. The biological effects and clinical implications of BRCA mutations: where do we go from here? Eur J Hum Genet. 2016;24(Suppl 1): S3-S9. doi:10.1038/ejhg.2016.93 21. Baudrin LG, Deleuze JF, How-Kit A. Molecular and computational methods for the detection of microsatellite instability in cancer [published online December 12, 2018]. Front Oncol. 2018. Accessed June 21, 2024. https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2018.00621/full 22. Hsiao SJ, Zehir A, Sireci AN, Aisner DL. Detection of tumor NTRK gene fusions to identify patients who may benefit from tyrosine kinase (TRK) inhibitor therapy. J Mol Diagn. 2019;21(4):553-571. doi:10.1016/j.jmoldx.2019.03.008 23. Tanaka M, Shibahara J, Fukushima N, et al. Claudin-18 is an early-stage marker of pancreatic carcinogenesis. J Histochem Cytochem. 2011;59(10):942-952. doi:10.1369/0022155411420569 24. Kayikcioglu E, Yüceer RO. The role of claudin 18.2 and HER-2 in pancreatic cancer outcomes [published online February 10, 2023]. Medicine (Baltimore). 2023. Accessed October 18, 2024. https://journals.lww.com/md-journal/fulltext/2023/02100/the_role_of_claudin_18_2_and_her_2_in_pancreatic.31.aspx 25. Zhang Z, Liu X, Zhou L, Zhang M, Liang Z. Investigation of clinical application of claudin 18 isoform 2 in pancreatic ductal adenocarcinoma: a retrospective analysis of 302 Chinese patients. Histol Histopathol. 2022;37(10):1031-1040. doi:10.14670/HH-18-477 26. Wu L, Zhu L, Xu K, et al. Clinical significance of site-specific metastases in pancreatic cancer, a study based on both clinical trial and real-world data. J Cancer. 2021;12(6):1715-1721. doi:10.7150/jca.50317 27. Strickler JH, Satake H, George TJ, et al. N Engl J Med. 2023;388(1):33-43. doi:10.1056/NEJMoa2208470 28. Conroy T, Pfeiffer P, Vilgrain V, et al. Pancreatic cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(11):987-1002. doi:10.1016/j.annonc.2023.08.009 29. Park W, Chawla A, O'Reilly EM. Pancreatic cancer: a review. JAMA. 2021;326(9):851-862. doi:10.1001/jama.2021.13027 30. Waddell N, Pajic M, Patch A-M, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518(7540):495-501. doi:10.1038/nature14169 31. Holter S, Borgida A, Dodd A, et al. Germline BRCA mutations in a large clinic-based cohort of patients with pancreatic adenocarcinoma. J Clin Oncol. 2015;33(28):3124-3129. doi:10.1200/JCO.2014.59.7401 32. Grant RC, Selander I, Connor AA, et al. Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. Gastroenterology. 2015;148(3):556-564. doi:10.1053/j.gastro.2014.11.042 33. Lowery MA, Wong W, Jordan EJ, et al. Prospective evaluation of germline alterations in patients with exocrine pancreatic neoplasms. J Natl Cancer Inst. 2018;110(10):1067-1074. doi:10.1093/jnci/djy024 34. Matsuoka T, Yashiro M. Biomarkers of gastric cancer: current topics and future perspective. World J Gastroenterol. 2018;24(26):2818-2832. doi:10.3748/wjg.v24.126.2818 35. Hu ZI, Shia J, Stadler ZK, et al. Evaluating mismatch repair deficiency in pancreatic adenocarcinoma: challenges and recommendations. Clin Cancer Res. 2018;24(6):1326-1336. doi:10.1158/1078-0432.CCR-17-3099 36. Luchini C, Brosens LAA, Wood LD, et al. Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications. Gut. 2021;70(1):148-156. doi:10.1136/gutjnl-2020-320726 37. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15(12):731-747. doi:10.1038/s41571-018-0113-0 38. Allen MJ, Zhang A, Bavi P, et al. Molecular characterisation of pancreatic ductal adenocarcinoma with NTRK fusions and review of the literature. J Clin Pathol. 2023;76(3):158-165. doi:10.1136/jclinpath-2021-207781 39. Gan Q, Roy-Chowdhuri S, Duose DY, et al. Adequacy evaluation and use of pancreatic adenocarcinoma specimens for next-generation sequencing acquired by endoscopic ultrasound-guided FNA and FNB. Cancer Cytopathol. 2022;130(4):275-283. doi:10.1002/cncy.22533 40. Asokkumar R, Yung Ka C, Loh T, et al. Comparison of tissue and molecular yield between fine-needle biopsy (FNB) and fine-needle aspiration (FNA): a randomized study. Endosc Int Open. 2019;7(8):E955-E963. doi:10.1055/a-0903-2565 41. De Las Casas LE, Hicks DG. Pathologists at the leading edge of optimizing the tumor tissue journey for diagnostic accuracy and molecular testing. Am J Clin Pathol. 2021:155(6):781-792. doi:10.1093/ajcp/aqaa212 42. Zhao Y, Xiong D, Aruna, et al. Fine needle biopsy versus fine needle aspiration in the diagnosis of immunohistochemistry-required lesions: a multicenter study with prospective evaluation. Endosc Ultrasound. 2023;12(6):456-464. doi:10.1097/eus.0000000000000028 43. Gwoździewicz K, Studniarek M, Czarnowska-Cubała M, Pieńkowska J, Markiet K. Usefulness of core biopsy in diagnosis of pancreatic tumours. Pol J Radiol. 2023;88:e529-e534. doi:10.5114/pjr.2023.132890 44. Klösges L, Chikhladze S, Biesel EA, Fichtner-FeigI S, Wittel UA. Surgical pancreatic biopsies for cases with locally advanced pancreatic cancer with inconclusive histology after interventional biopsy. Surg Open Sci. 2023;15:61-66. doi:10.1016/j.sopen.2023.07.003