Unsupported Browser
The American College of Surgeons website is not compatible with Internet Explorer 11, IE 11. For the best experience please update your browser.
Become a member and receive career-enhancing benefits

Our top priority is providing value to members. Your Member Services team is here to ensure you maximize your ACS member benefits, participate in College activities, and engage with your ACS colleagues. It's all here.

Become a Member
Become a member and receive career-enhancing benefits

Our top priority is providing value to members. Your Member Services team is here to ensure you maximize your ACS member benefits, participate in College activities, and engage with your ACS colleagues. It's all here.

Membership Benefits
For Your Patients

Cancer Research Programs

Genetic and Genomic Testing and Implications in Treatment for Pancreatic Adenocarcinoma: What All Surgeons Should Know

Elizabeth L. Carpenter, MD, Rebecca A. Snyder, MD, MPH, FACS, and Timothy J. Vreeland, MD, FACS

October 1, 2022

Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy, with a 5-year survival of less than 10%.1-3 Despite recent diagnostic and therapeutic advances, overall survival has only marginally improved.3-6 Known risk factors for PDAC include cigarette smoking, obesity, environmental and chemical exposures, and alcohol.1 The role of genetic abnormalities, however, has become increasingly important as genetic testing platforms, and our knowledge of genetic risk factors, have improved.

Genetic Testing in PDAC

Pathogenic germline variants for pancreatic cancer are identified in more than 10% of patients with PDAC.7,8 Both the National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) recently updated recommendations to include genetic testing for all patients with newly diagnosed pancreatic cancer.1,9,10 Given the lack of any single driver mutation in PDAC, but rather numerous tumorigenic pathways, patients require broad genetic testing.

The most common genetic drivers of pancreatic cancer are genes that play a role in DNA damage repair. These include mutations in BRCA1 and BRCA2 (Breast Cancer gene 1 and 2), but also less well-known genes such as ATM, PALB2, and CDKN2A, among others.11,12 Specifically, these gene mutations (whether germline or somatic) lead to homologous recombination deficiency (HDR) and hindrance of double-stranded DNA break repair.12-16 Such mutations leave these tumors susceptible to specific therapies, including platinum-based chemotherapy and poly (ADP-ribose) polymerase inhibitors (PARP).17,18 Platinum agents work by binding and cross-linking DNA, causing DNA damage and cell death, while PARP are theorized to inhibit the repair of single-strand DNA breaks, although the exact mechanism remains unclear. When PARP are combined with preexisting mutations affecting double-stranded DNA break repair, tumor cell death occurs via a process known as synthetic lethality.19,20

These effects translate to meaningful improvements in patient outcomes.17,18 In one study conducted by Park and colleagues, patients with somatic or germline HDR stage III/IV PDAC had a significantly prolonged progression-free survival (PFS) when treated with first-line platinum chemotherapy (HR 0.44, p<0.01) compared with patients without an HRD mutation; this effect was not observed among patients treated with a non-platinum regimen.21

Importantly for surgeons, these findings may have implications in the neoadjuvant setting. As neoadjuvant therapy is increasingly used in treatment of nonmetastatic PDAC, mutation status should be defined at the time of diagnosis to ensure that patients with germline or somatic HRD mutations are considered for upfront platinum therapy.22 This is specifically relevant when a gemcitabine-based regimen is chosen over FOLFIRINOX (fluorouracil, leucovorin calcium [folinic acid], irinotecan hydrochloride, and oxaliplatin). In this situation, combination with cisplatin rather than the more common gemcitabine-nab-paclitaxel should be considered, particularly for patients with BRCA/PALB2 mutations.1

These patients also may be candidates for PARP therapy.18 In the Pancreas Cancer Olaparib Ongoing (POLO) trial, a phase-3 randomized controlled trial comparing PFS in patients with BRCA1/2 germline mutations and metastatic disease without progression on platinum therapy, patients receiving the PARP olaparib had significantly longer PFS compared with placebo (7.4 versus 3.8 months, p = 0.004).23 Combination strategies and use of PARP in the adjuvant setting are being actively investigated.18,20,24 For example, the phase 2-APOLLO* trial—which aims to investigate the benefits of adjuvant olaparib versus placebo on relapse-free survival in patients with resected pancreatic cancer with BRCA1/2 or PALB2 pathologic mutations after platinum-based chemotherapy—is currently recruiting and projected to conclude in 2024 (NCT04858334). The role of PARP in the neoadjuvant setting is not yet defined but also is being studied.18

Genomic Testing

In addition to germline testing, tumor molecular profiling is recommended to identify actionable somatic mutations in patients with locally advanced or metastatic disease who are candidates for anti-cancer therapy.1 While relatively rare in PDAC, patients with mismatch repair-deficient (dMMR) and microsatellite instability-high (MSI-H) mutations may be responsive to PD-1 blockade with the immune checkpoint inhibitor pembrolizumab, which now is recommended as a second-line option in dMMR/MSI-H positive tumors.18,25-28 There is potential for targeting KRAS mutations, which may be found in approximately 90% of pancreatic cancers.29 Preliminary results investigating the efficacy of KRAS inhibitors in solid tumors including pancreatic cancer, such as sotorasib in the CodeBreaK 100 trial, are highly promising.30-32 Variants such as neurotrophic tyrosine receptor kinase (NTRK) fusions, though found in an extremely small subset of patients, also are important to recognize and target.18

What All Surgeons Should Know

Increasing attention is directed to genetic and genomic drivers of PDAC. With potentially actionable mutations being found in up to 25% of patients, genomic sequencing is recommended for locally advanced or metastatic disease, and genetic testing for newly diagnosed PDAC or when suspicion exists for inherited risk.1,8,18 Long-term survival of patients with PDAC remains poor, but there is reason for optimism following the discovery of HDR mutations and the potential for more targeted treatment regimens.18 Because surgeons often are the first clinicians to see a patient after a diagnosis of pancreatic cancer, it is critical for surgeons to be aware of the recommendation for genetic testing and to understand the implications of identifying targetable alterations.


The views expressed herein are those of the authors and do not reflect the official policy or position of Brooke Army Medical Center, the US Army Medical Department, the Department of the Army, Department of the Air Force, Department of Defense, or the US government.

*A Randomized Phase II Double-Blind Study of Olaparib Versus Placebo Following Curative Intent Therapy in Patients With Resected Pancreatic Cancer and a Pathogenic BRCA1, BRCA2 or PALB2 Mutation.

Dr. Elizabeth Carpenter is a general surgery resident at Brooke Army Medical Center in San Antonio, TX.


  1. Tempero MA, Malafa MP, Al-Hawary M, et al. Pancreatic Adenocarcinoma, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021;19(4):439-457.
  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: A Cancer Journal for Clinicians. 2016;66(1):7-30.
  3. Khorana AA, Mangu PB, Berlin J, et al. Potentially Curable Pancreatic Cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2016;34(21):2541-2556.
  4. Worni M, Guller U, White RR, et al. Modest improvement in overall survival for patients with metastatic pancreatic cancer: A trend analysis using the surveillance, epidemiology, and end results registry from 1988 to 2008. Pancreas. 2013;42(7):1157-1163.
  5. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, et al. Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the US. Cancer Res. 2014;74(11):2913-2921.
  6. StatBite. US pancreatic cancer rates. J Natl Cancer Inst. Dec 2010;102(24):1822.
  7. Rainone M, Singh I, Salo-Mullen EE, et al. An emerging paradigm for germline testing in pancreatic ductal adenocarcinoma and immediate implications for clinical practice: A review. JAMA Oncol. 2020;6(5):764-771.
  8. Mavros MN, Moris D, Karanicolas PJ, et al. Clinical trials of systemic chemotherapy for resectable pancreatic cancer: A review. JAMA Surg. 2021;156(7):663-672.
  9. Stoffel EM, McKernin SE, Brand R, et al. Evaluating susceptibility to pancreatic cancer: ASCO provisional clinical opinion. J Clin Onc. 2019;37(2):153-164.
  10. Sohal DPS, Kennedy EB, Cinar P, et al. Metastatic pancreatic cancer: ASCO guideline update. J Clin Onc. 2020;38(27):3217-3230.
  11. Perkhofer L, Golan T, Cuyle PJ, et al. Targeting DNA damage repair mechanisms in pancreas cancer. Cancers (Basel). 2021;13(17).
  12. Shen GQ, Aleassa EM, Walsh RM, Morris-Stiff G. Next-generation sequencing in pancreatic cancer. Pancreas. 2019;48(6):739-748.
  13. Sutton TL, Grossberg A, Ey F, et al. Multimodality therapy in metastatic pancreas cancer with a BRCA mutation and durable long-term outcome: Biology, intervention, or both? Cancer Biol Ther. 2021;22(10-12):532-536.
  14. Walker EJ, Blanco AM, Carnevale J, et al. The additional diagnostic benefit of pancreatic cancer molecular profiling after germline testing. Pancreas. 2022;51(4):302-304.
  15. Rapposelli IG, Zampiga V, Cangini I, et al. Comprehensive analysis of DNA damage repair genes reveals pathogenic variants beyond BRCA and suggests the need for extensive genetic testing in pancreatic cancer. BMC Cancer. 2021;21(1):611.
  16. van Wilpe S, Tolmeijer SH, Koornstra RHT, et al. Homologous recombination repair deficiency and implications for tumor immunogenicity. Cancers (Basel). 2021;13(9).
  17. Wattenberg MM, Asch D, Yu S, et al. Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation. BJC. 2020;122(3):333-339.
  18. Zheng-Lin B, O’Reilly EM. Pancreatic ductal adenocarcinoma in the era of precision medicine. Semin Oncol. 2021;48(1):19-33.
  19. O’Connor MJ. Targeting the DNA damage response in cancer. Molecular cell. 2015;60(4):547-560.
  20. Lord CJ, Ashworth A. PARP inhibitors: the first synthetic lethal targeted therapy. Science (New York, NY). 2017;355(6330):1152.
  21. Park W, Chen J, Chou JF, et al. Genomic methods identify homologous recombination deficiency in pancreas adenocarcinoma and optimize treatment selection. Clin Cancer Res. 2020;26(13):3239-3247.
  22. Aquina CT, Ejaz A, Tsung A, et al. National trends in the use of neoadjuvant therapy before cancer surgery in the US from 2004 to 2016. JAMA Netw Open. 2021;4(3):e211031.
  23. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. NEJM. 2019;381(4):317-327.
  24. O’Kane GM, Lowery MA. Moving the needle on precision medicine in pancreatic cancer. J Clin Oncol. 2022;40(24):2693-2705.
  25. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. NEJM. June 2015;372(26):2509-20.
  26. Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: Results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38(1):1-10.
  27. Sohal DPS, Kennedy EB, Cinar P, et al. Metastatic pancreatic cancer: ASCO guideline update. J Clin Oncol. 2020: Epub ahead of print.
  28. McCarthy PM, Rendo MJ, Uy MD, et al. Near complete pathologic response to PD-1 inhibitor and radiotherapy in a patient with locally advanced pancreatic ductal adenocarcinoma. Onco Targets Ther. 2021;14:3537-3544.
  29. Cancer Genome Atlas Research Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell. 2017;32(2):185-203.e13.
  30. AMG 510 shows activity beyond NSCLC. Cancer Discov. 2020;10(8):1084-1085.
  31. Hong DS, Kuo J, Sacher AG, et al. CodeBreaK 100: Phase I study of AMG 510, a novel KRASG12C inhibitor, in patients (pts) with advanced solid tumors other than non-small cell lung cancer and colorectal cancer (CRC). J Clin Onc. 2020;38(15_suppl):3511.
  32. Bekaii-Saab TS, Spira AI, Yaeger R, et al. KRYSTAL-1: Updated activity and safety of adagrasib (MRTX849) in patients with unresectable or metastatic pancreatic cancer (PDAC) and other gastrointestinal (GI) tumors harboring a KRASG12C mutation. J Clin Onc. 2022;40(4_suppl):519.