Biomarker Consortium

GI Cancer

Pancreatic Cancer

Gene location: chromosome 11 (11q22-11q23)

gene that is located on chromosome 11q22-q23 encodes ATM, a large serine/threonine kinase is a central regulator of the DNA damage response (DDR).

Structurally, ATM belongs to the PI3K-related kinase (PIKK) family, sharing conserved domains involved in DNA repair signaling.

Under normal conditions, ATM exists as an inactive dimer or multimer. In response to DNA double-strand breaks, it becomes activated through autophosphorylation at Ser1981, leading to dissociation into active monomers.

These monomers then phosphorylate key downstream targets involved in the DNA damage response (including 

), thereby coordinating cell cycle arrest, DNA repair, or apoptosis.

 disrupts these checkpoint and repair pathways, leading to genomic instability, accumulation of mutations, and malignant transformation.

In preclinical mouse models, combined loss of 

 drives the formation of aggressive pancreatic ductal adenocarcinoma (PDAC), emphasizing ATM’s role as a tumor suppressor.

Approximately 1% to 3% of patients with pancreatic cancer harbor germline 

 mutations; individuals with this mutation have a 6.5-fold increased lifetime risk of developing the disease compared to noncarriers.

Somatic alterations (mutations or loss of expression) of 

 occur in 5% to 18% of PDAC tumors and are associated with deficient DNA repair mechanisms.

These mutations are more frequently observed in familial pancreatic cancer, suggesting a role in hereditary predisposition.

ATM testing is recommended for all patients diagnosed with PDAC, regardless of age or family history.

Personal or family history suggestive of hereditary cancer syndromes (eg, familial pancreatic cancer)

Early-onset PDAC (age, typically < 50 years)

Eligibility for clinical trials involving DDR-targeted therapies (eg, ATR or PARP inhibitors).

Germline testing involves multigene panel sequencing on blood or saliva, typically ordered through commercial or institutional genetic testing services.

Somatic testing is conducted via next-generation sequencing (NGS) on tumor tissue to detect acquired (noninherited) mutations.

Immunohistochemistry (IHC) for ATM protein expression is not part of standard clinical practice but may be used in research settings to assess 

The NCCN Guidelines (version 2.2025) recommend:

, for all patients with PDAC regardless of clinical or family history.

Somatic NGS testing to guide treatment with platinum agents, PARP inhibitors, or investigational DDR-targeted therapies.

IHC is not routinely recommended but may be incorporated into future clinical trials or exploratory end points.

There are currently no FDA-approved therapies that specifically target 

Platinum chemotherapy agents have enhanced activity in ATM-deficient tumors; this is likely due to their mechanism of inducing DNA crosslinks and double-strand breaks, which ATM-deficient cells cannot repair effectively.

PARP inhibitors (eg, olaparib, talazoparib)

-mutant PDAC, although their efficacy is less well established compared to 

Early data suggest limited single-agent activity in ATM-deficient cancers, but combination strategies (eg, with ATR inhibitors or checkpoint blockade) are being evaluated.

Exploits synthetic lethality in the setting of 

 loss; being tested alone and in combination with chemotherapy or immunotherapy

Ceralasertib is a selective oral ATR kinase inhibitor that disrupts the DNA damage response by blocking replication stress checkpoints.

It is particularly effective in tumors with ATM deficiency that rely more on ATR.

By inhibiting ATR, ceralasertib causes accumulation of DNA damage and replication fork collapse, leading to tumor cell death via synthetic lethality.

Phase 2 trial evaluating ceralasertib (AZD6738) alone and in combination with olaparib or durvalumab in patients with selected solid tumor malignancies, including advanced PDAC

Armstrong SA, Schultz CW, Azimi-Sadjadi A, Brody JR, Pishvaian MJ. ATM dysfunction in pancreatic adenocarcinoma and associated therapeutic implications. 

. 2019;18(11):1899-1908. doi:10.1158/1535-7163.MCT-19-0208

Russell R, Perkhofer L, Liebau S, et al. Loss of ATM accelerates pancreatic cancer formation. 

Roberts NJ, Jaio Y, Yu J, et al. ATM mutations in patients with hereditary pancreatic cancer. 

  2012;2(1):41-46. doi:10.1158/2159-8290.CD-11-0194

Lowery MA, Wong W, Jordan EJ, et al. Prospective evaluation of germline alterations in exocrine pancreatic neoplasms. 

 2018;110(10):1067-1074. doi:10.1093/jnci/djy024

NCCN. Clinical Practice Guidelines in Oncology.

Pancreatic adenocarcinoma, version 2.2025. Accessed July 25, 2025. 

https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf

Choi M, Kipps T, Kurzrock R. ATM mutations in cancer: therapeutic implications. 

;15(8):1781-1791. doi:10.1158/1535-7163.MCT-15-0945

Hannan Z, Yu S, Domchek S, Mamtani R, Reiss KA. Clinical Characteristics of Patients With Pancreatic Cancer and Pathogenic 

  2021 Jan 23;5(2):pkaa121. doi: 10.1093/jncics/pkaa121

Yap TA, O'Carrigan B, Penney MS, et al. Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors. 

 2020;38(27):3195-3204. doi: 10.1200/JCO.19.02404

Ceralasertib (AZD6738) alone and in combination with olaparib or durvalumab in patients with solid tumors. ClinicalTrials.gov. Updated June 6, 2025. Accessed June 30, 2025. 

https://clinicaltrials.gov/study/NCT03682289

DNA mismatch repair/microsatellite instability

DNA MMR is involved in preserving genomic fidelity by repairing DNA after mismatching errors after replication or recombination.

MMR is also involved in cell cycle regulation and apoptosis in response to DNA damage.

Four genes regulate MMR mechanisms, and the dimer proteins they form are responsible for mismatch recognition, insertion-deletion loops, base excision, and other functions. 

Biallelic inactivation of 1 or more MMR genes can result from either somatic or germline mutations or from epigenetic silencing.

Germline mutations in MMR genes are frequently associated with Lynch syndrome, which is known to increase the risk of several types of cancers.

Microsatellites are short tandem nucleotide repeats (1-6 nucleotides) scattered throughout the genome and prone to high rates of mutation.

The incidence of MMR-deficient (dMMR)/MSI-H pancreatic cancer ranges from 

MSI refers to a hypermutable phenotype that results when MMR genes are inactive or faulty.

MSI status is generally categorized into 3 types: high MSI (MSI-H), low MSI (MSI-L), and microsatellite stability (MSS).

Testing is recommended for patients with locally advanced or metastatic pancreatic cancer who are candidates for anticancer therapy.

Several techniques are used to test for the presence of dMMR including immunohistochemistry (IHC) or polymerase chain reaction (PCR)–based assays as well as next-generation sequencing (NGS) testing. 

IHC assays assess expression of MMR proteins, PCR evaluates tumor DNA for microsatellite repeats, and NGS identifies inactivating mutations in MMR genes. 

MSI-H status correlates with the loss expression in 2 of 4 MMR proteins and abnormal microsatellites in 2 or more regions.

For patients with locally advanced or metastatic disease eligible for anticancer therapy, the NCCN Panel recommends testing for actionable somatic mutations, including fusions (ALK, NRG1, NTRK, ROS1, FGFR2, RET), mutations (BRAF, BRCA1/2, HER2, KRAS, PALB2), amplifications (HER2), MSI, dMMR, and TMB.

The FDA has approved several immunotherapy agents for the treatment of patients with dMMR/MSI-H solid tumors.

In 2023, pembrolizumab received approval for the treatment of adult and pediatric patients who have unresectable or metastatic MSI-H or dMMR solid tumors as determined by an FDA-approved test, who have experienced progression following prior treatment, and who have no satisfactory alternative treatment options.

Dostarlimab has also received accelerated approval for dMMR recurrent or advanced solid tumors with no satisfactory alternative treatment options based on findings from the GARNET trial (NCT02715284).

Pembrolizumab and dostarlimab are monoclonal antibodies that target the programmed death receptor-1 (PD-1), blocking its interaction with the ligands PD-L1 and PD-L2, thereby promoting anti-tumor activity.

Modrich P, Lahue R. Mismatch repair in replication fidelity, genetic recombination, and cancer biology. 

. 1996; 65:101-133. doi:10.1146/annurev.bi.65.070196.000533

Marti TM, Kunz C, Fleck O. DNA mismatch repair and mutation avoidance pathways. 

Bellacosa A. Functional interactions and signaling properties of mammalian DNA mismatch repair proteins. 

. 2001;8:1076-1092. doi:10.1038/sj.cdd.4400948

Peters AC, Young LC, Maeda T, Tron VA, Andrew SE. Mammalian DNA mismatch repair protects cells from UVB-induced DNA damage by facilitating apoptosis and p53 activation. 

 2003;2:427-435. doi:10.1016/s1568-7864(03)00003-x

 1996;65:101-133. doi:10.1146/annurev.bi.65.070196.000533

Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. 

 1998;95:6870-6875. doi:10.1073/pnas.95.12.6870

Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. 

 2008;26:5783-5788. doi:10.1200/JCO.2008.17.5950

Lynch HT, de la Chapelle A. Hereditary colorectal cancer. 

 2003;348:919-932. doi:10.1056/NEJMra012242

Aaltonen LA, Salovaara R, Kristo P, et al. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. 

 1998;338:1481-1487. doi:10.1056/NEJM199805213382101

Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). 

 2005;352:1851-1860.doi:10.1056/NEJMoa043146

Bonneville R, Krook MA, Chen HZ, et al. Detection of microsatellite instability biomarkers via next-generation sequencing. 

 2020;2055:119-132. doi:10.1007/978-1-4939-9773-2_5

Li K, Luo H, Huang L, Luo H, Zhu X. Microsatellite instability: a review of what the oncologist should know. 

 2020;20:16. doi:10.1186/s12935-019-1091-8

Hu ZI, Shia J, Stadler ZK, et al. Evaluating mismatch repair deficiency in pancreatic adenocarcinoma: challenges and recommendations. 

 2018;24(6):1326-1336. doi:10.1158/1078-0432.CCR-17-3099

NCCN. Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma, version 1.2024. Accessed April 10, 2024. 

KEYTRUDA (pembrolizumab). Prescribing information. Merck & Co; 12018. Accessed April 10, 2024. 

https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf

JEMPERLI (dostarlimab). Prescribing information. GlaxoSmithKline; 2024. Accessed April 10, 2024. 

https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Jemperli/pdf/JEMPERLI-PI-MG.PDF

FDA converts to full approval indication for KETRUDA (pembrolizumab) for certain adult and pediatric patients with advanced microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors. Press release. Merck. March 29, 2023. Accessed April 10, 2024. 

https://www.merck.com/news/fda-converts-to-full-approval-indication-for-keytruda-pembrolizumab-for-certain-adult-and-pediatric-patients-with-advanced-microsatellite-instability-high-msi-h-or-mismatch-repair-deficient/

FDA grants accelerated approval to dostarlimab-gxly for dMMR advanced solid tumors. FDA. Updated July 18, 2023. Accessed April 10, 2024. 

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dostarlimab-gxly-dmmr-advanced-solid-tumors

dMMR/MSI-H

V-RAF murine sarcoma viral oncogene homolog B1 (BRAF)

 gene is located on chromosome 7, and its corresponding protein plays a role in the RAS-RAF-MEK-ERK (MAPK) signal transduction pathway.

MAPK enzymes are activated through interaction with growth factors, cytokines, and hormones.

More than a dozen known MAPK enzymes regulate cell differentiation, proliferation, and survival.

BRAF and its family of proteins are serine/threonine kinases that target other MAPK proteins via phosphorylation.

BRAF has 3 conserved regions (CRs) involved in protein function: CR1, CR2, and CR3.

CR1 and CR3 interact to form an autoinhibitory complex, whereas CR2 functions as a hinge for this complex.

Under normal conditions, RAS-GTP binds the CR1-CR3 complex and exposes the CR3 catalytic site for substrate activation.

Once activated, BRAF is localized to the cell membrane.

 is a major driver of gene alteration in many types of cancer, including pancreatic malignancies, and the V600E mutation has been best characterized as a constitutive active driver mutation.

can create a constitutively active protein that drives unregulated cell growth and division.

Pathogenic BRAF variants, including class I/II mutations, deletions, and fusions, are present in

occurring more frequently in KRAS wild-type vs KRAS-mutant tumors (30% vs 1.5%, respectively).

BRAF V600E comprise approximately 17-28% of BRAF mutations in pancreatic cancer.

BRAF testing can be performed using immunohistochemistry (IHC) or, preferably, next-generation sequencing (NGS).

The National Comprehensive Cancer Network guidelines recommend testing for actionable somatic mutations including those involving 

 for all patients with advanced pancreatic cancer regardless of the presence of metastases.

The recommended testing method is NGS with an FDA-approved assay, although there is a growing consensus that RNA-based testing for fusion gene expression should be strongly considered as well.

V600E–mutant pancreatic cancer is dabrafenib plus trametinib.

The treatment of adult and pediatric patients ≥ 1 year who have unresectable or metastatic solid tumors that harbor a 

 V600E mutation, whose disease has progressed following prior treatment, and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Dabrafenib inhibits signals from the BRAF protein activated by the 

V600E mutation and prevents associated tumor growth.

Trametinib complements this mechanism by inhibiting mitogen-activated extracellular-regulated kinase 1 (MEK1) and MEK2 that is activated by the mutated gene.

The dual action prevents tumors from continuing to grow via the escape mechanism of MEK protein activating signals.

Learn more about Dabrafenib and Trametinib >

https://us.tafinlarmekinist.com/metastatic-nsclc/patient-support/patient-resources

TAFINLAR (dabrafenib). Prescribing information. Novartis; 2024. Accessed March 11, 2024. 

https://www.novartis.com/us-en/sites/novartis_us/files/tafinlar.pdf

MEKINIST (trametinib). Prescribing information. Novartis; 2024. Accessed March 11, 2024. 

https://www.novartis.com/us-en/sites/novartis_us/files/mekinist.pdf

New study targets specific BRAF mutation. Let’s Win Pancreatic Cancer. July 27, 2023. Accessed March 11, 2024. 

https://letswinpc.org/research/target-braf-mutation/

Wan PTC, Garnett MJ, Roe SM, et al; Cancer Genome Project. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. 

 2004;116(6):855-867. doi:10.1016/s0092-8674(04)00215-6

Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. 

 2011;75(1):50-83. doi:10.1128/MMBR.00031-10

Zaman A, Wu W, Bivona TG. Targeting oncogenic BRAF: past, present, and future. 

 2019;11(8):1197. doi:10.3390/cancers11081197

Allen MJ, Zhang A, Bavi P, et al. Molecular characterisation of pancreatic ductal adenocarcinoma with 

 fusions and review of the literature. J Clin Pathol. 2023;76(3):158-165. doi: 10.1136/jclinpath-2021-207781.

NCCN. Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma, version 1.2024. Accessed June 11, 2024. 

Winstead E. Dabrafenib-trametinib combination approved for solid tumors with BRAF mutations. American Cancer Society. July 21, 2022. Accessed March 9, 2024. 

https://www.cancer.gov/news-events/cancer-currents-blog/2022/fda-dabrafenib-trametinib-braf-solid-tumors

BRAF V600E

Neurotrophic tropomyosin kinase receptors (NTRK)

Neurotrophic tropomyosin kinase receptors (NTRK) are a family of transmembrane proteins involved in neuronal development, proliferation, survival, and differentiation.

The genes NTRK1, NTRK2, and NTRK3 encode the proteins TRKA, TRKB, and TRKC, respectively.

TRK proteins are activated via neurotrophin ligands that trigger receptor dimerization and phosphorylation.

After activation, TRK proteins active signal transduction pathways RAS-RAF-MEK-ERK (MAPK), phosphatidylinositol-3-kinase (PI3K), phospholipase C-γ1, and others.

NTRK is a driver oncogene that promotes tumorigenesis via constitutive expression or increased kinase domain activity.

Gene fusions involve one of the three NTRK genes fusing the c-terminal with an n-terminal fusion partner, resulting in a chimeric protein that promotes solid tumor growth.

NTRK gene fusion mutations are rarely present in cancers (<1%) and have a similarly low prevalence in pancreatic cancer 

Testing is recommended for patients with locally advanced or metastatic pancreatic cancer who are candidates for anticancer therapy

Testing can be performed via  immunohistochemistry (IHC) or via an FDA-approved or validated next-generation sequencing (NGS) assay; RNA assays are preferred over DNA assays for gene fusion detection.

It has been suggested that if immunohistochemistry (IHC) is used to detect NTRK gene fusions, then positive samples should be confirmed with RNA-NGS.

Larotrectinib and entrectinib are the two drugs currently approved by the FDA for treating NTRK gene fusion-positive solid tumors that are unresectable or metastatic.

They are both tropomyosin receptor tyrosine kinase inhibitors with slightly different molecular target profiles.

Larotrectinib was approved based on data from three phase I-II studies, with the primary endpoint overall response rate (ORR) and secondary endpoints duration of response (DOR), progression-free survival (PFS), and safety.

Based on outcomes data, larotrectinib was approved in 2018, with updated data published in 2020 that showed ORR 79% (95% CI 72-85) and 16% showing a complete response.

In 2019, the FDA approved entrectinib based on clinical data from phase I-II trials ALKA-372-001, STARTRK-1, and STARTRK-2.

 ORR was 57.4 (95% CI 43.2-70.8), DOR 10.4 months (95% CI 7.1-NR), and PFS 11.2 months (95% CI 8.0-14.9).

The FDA has approved entrectinib for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic, or where surgical resection is likely to result in severe morbidity; it is also approved for situations where there are no satisfactory alternative treatments or the patient has progressed following treatment. 

This indication has received accelerated approval based on the overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes 

 respectively), proto-oncogene tyrosine-protein kinase ROS1 (ROS1), and anaplastic lymphoma kinase (ALK). Entrectinib also inhibits JAK2 and TNK2.

Fusion proteins that include TRK, ROS1, or ALK kinase domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Entrectinib demonstrated in vitro and in vivo inhibition of cancer cell lines derived from multiple tumor types harboring NTRK, ROS1, and ALK fusion genes.

https://www.gene.com/patients/medicines/rozlytrek

The FDA has approved larotrectinib for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic, or where surgical resection is likely to result in severe morbidity; it is also approved for situations where there are no satisfactory alternative treatments or the patient has progressed following treatment.

Larotrectinib is an inhibitor of the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC. TRKA, B, and C are encoded by the genes 

Chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in constitutively-activated chimeric TRK fusion proteins that can act as an oncogenic driver, promoting cell proliferation and survival in tumor cell lines. In in vitro and in vivo tumor models, larotrectinib demonstrated anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression.

https://hcp.vitrakvi-us.com/support-and-resources/resources

Okamura R, Boichard A, Kato S, Sicklick JK, Bazhenova L, Kurzrock R. Analysis of 

 Alterations in Pan-Cancer Adult and Pediatric Malignancies: Implications for NTRK-Targeted Therapeutics. 

Manea CA, Badiu DC, Ploscaru IC, et al. A review of NTRK fusions in cancer. 

. 2022;79. doi:10.1016/j.amsu.2022.103893

Lange A, Lo HW. Inhibiting TRK Proteins in Clinical Cancer Therapy. 

. 2018;10(4):105. doi:10.3390/cancers10040105

Demols A, Rocq L, Perez-Casanova L, et al. A Two-Step Diagnostic Approach for 

 Gene Fusion Detection in Biliary Tract and Pancreatic Adenocarcinomas. 

. 2023;28(7):e520-e525. doi:10.1093/oncolo/oyad075

. 2023;76(3):158-165. doi:10.1136/jclinpath-2021-207781

National Comprehensive Cancer Network. NCCN guidelines version 1.2024: Pancreatic Adenocarcinoma. 

ROZLYTREK (entrectinib). Prescribing information. Genentech; 2019. Accessed May 5, 2024. 

https://www.gene.com/download/pdf/rozlytrek_prescribing.pdf

VITRAKVI (larotrectinib). Prescribing information. Loxo Oncology; 2018. Accessed May 5, 2024. 

https://labeling.bayerhealthcare.com/html/products/pi/vitrakvi_PI.pdf

Drilon A, Laetsch TW, Kummar S, et al. Efficacy of Larotrectinib in 

 Fusion–Positive Cancers in Adults and Children. 

. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448

Demetri GD, Paz-Ares L, Farago AF, et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive (NTRK-fp) tumors: pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. 