Lynn M. Matrisian, PhD, MBA, and Allison Rosenzweig, PhD, from Pancreatic Cancer Action Network, review advances in the pancreatic cancer setting for World Pancreatic Cancer Awareness Day.
The Pancreatic Cancer Setting
Cancer of the pancreas is relatively rare in the United States (U.S.), ranking eleventh in cancer incidence with 60,000 cases estimated in 2021.1 Despite the low incidence, pancreatic cancer is becoming much more widely known—and feared—as a result of high-profile cases, including singer Aretha Franklin, Supreme Court Justice Ruth Bader Ginsburg, Jeopardy host Alex Trebek, and Representative John Lewis. It is known as a disease that strikes rapidly and aggressively, with minimal treatment options and short survival times. This impression is justified since pancreatic cancer holds the distinction of being the deadliest of the major cancers tracked by the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program as determined by the lowest 5-year relative survival rate.1
The combination of being rare and deadly complicates the treatment of pancreatic cancer in the community setting, where most patients with cancer in the U.S. are seen. Based on the estimate of 13,146 oncologists engaged in patient care in 2021,2 an oncologist on average would see 4 to 5 cases of pancreatic cancer per year, and only 1 would be alive a year later (35% 1-year survival, SEER-18 2000-2018). Unless substantial changes occur soon, the situation will worsen. In contrast to the trend for a continued decrease in mortality from cancer in general, the number of deaths from pancreatic cancer is increasing and are projected to surpass colorectal cancer deaths to become second only to lung cancer before 2030.3 These projections are a wake-up call that a significant commitment to advancing the management of pancreatic cancer now is required to avoid the burden of pancreatic cancer deaths predicted by current trends.
The exceptionally poor survival rate from pancreatic cancer can be attributed to factors such as the ambiguity of symptoms and aggressive nature of the pancreatic adenocarcinoma (PDAC) form of the disease. Fifty-two percent of cases of newly diagnosed PDAC present with distant metastases, 30% with regional lymph node involvement, and only 11% have tumors that are localized solely within the pancreas (SEER-18 2011-2017). Survival rates are stage-dependent: 42% for localized disease, 14% regional, and 3% metastatic make up the overall 5-year relative survival rate of 10.8% (SEER-18 2011-2017). These stark numbers explain the 2 major areas of research focus within the pancreatic cancer field: identifying better chemotherapeutic treatments to extend the lives of patients with metastatic disease and developing a strategy to detect pancreatic cancer earlier when it is localized to the pancreas and can be surgically resected.
Symptoms and Advances in the Early Detection of Pancreatic Cancer
If the stage distribution at the time of diagnosis of PDAC could be reversed so that more than 50% of individuals present with localized disease and only 10% are already metastatic, survival would be more than doubled without any additional improvements in therapy.4 For this reason, considerable effort has gone into research to identify individuals at risk of pancreatic cancer and developing surveillance programs and biomarkers to find pancreatic cancer earlier.
Between 10% to 15% of PDAC cases are found in individuals with an elevated risk based on an inherited gene. In some cases, there is a strong family history of pancreatic cancer. The risk of familial pancreatic cancer, defined as a family with at least 1 first-degree relative pair (parent/child or sibling/sibling), varies depending on the number of affected individuals in the family and degree of relatedness but is increased on average approximately 9-fold over the general population.5 In some cases, the gene responsible for familial PDAC is known and can include those involved in hereditary breast and ovarian, melanoma, and colon cancer syndromes. However, there are cases of PDAC in individuals who are found to carry a hereditary predisposition gene and have no known relative with PDAC but may have relatives with other cancer types.6 This realization resulted in changing in National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) guidelines to indicate all patients diagnosed with PDAC should receive genetic testing for hereditary syndromes.7,8 Cascade testing of family members of patients with a predisposition gene helps determine their risk of developing the disease, which varies depending on the affected gene.
Most PDAC cases are sporadic, with no indication of inherited risk. Symptoms of pancreatic cancer are often vague and likely to be attributed to changes in daily activities, including abdominal or mid-back pain, unexplained weight loss, loss of appetite, indigestion, and changes in stool. The development of jaundice is more likely to be recognized as a worrisome symptom and evoke imaging follow-up. New-onset diabetes is an often-unrecognized symptom of pancreatic cancer that is providing an opportunity to develop cohorts of individuals at risk of sporadic PDAC and validate biomarker and algorithm-based approaches to improving the early detection of PDAC.9 PDAC arises from benign precursors referred to as pancreatic intraepithelial neoplasms (PanIN), as well as from subsets of pancreatic cysts. Pancreatic cysts are common, and mucinous cystic neoplasm and intraductal papillary mucinous neoplasms have varying malignant potential; their detection and clinical management is addressed by guidelines from several organizations.10
Surveillance programs for high-risk individuals relies on imaging by endoscopic ultrasonography and/or MRI/magnetic resonance cholangiopancreatography.11 Results following 16 years of follow-up of individuals with genetic factors or family history of PDAC enrolled in the Cancer of the Pancreas Screening (CAPS) study revealed that most PDAC detected during surveillance were resectable with significantly improved survival relative to those who had PDAC detected outside of surveillance.12
There are several commercially developed screening assays that provide encouragement that breakthroughs in the early detection of pancreatic cancer will occur sooner rather than later. The IMMray PanCan-d blood test for protein biomarkers was released in 2021 for the early detection of PDAC in individuals at high risk for familial or hereditary pancreatic cancer. The Galleri multicancer blood test for methylated circulating DNA includes pancreatic cancer and is recommended for the general population of adults age 50 or older.13 There are also tests of cyst fluid to distinguish cysts with low vs high risk of progression to pancreatic cancer, including CompCyst,14 PancreaSeq,15 and Pancragen.16 None of these tests are FDA approved or acknowledged by the U.S. Preventive Services Task Force as being of sufficient clinical utility for use in screening for pancreatic cancer but represent an advance and an opportunity for further studies to reach that goal.
Advances in the Treatment of Pancreatic Adenocarcinoma
Advances in the treatment of PDAC in the U.S. have arisen from the testing of regimens that were successful in other cancer types as well as from clinical research leading to FDA approval for new treatment entities. Progress has historically been slow, with less than 10% of phase 3 trials for the first-line treatment of PDAC resulting in a clinically meaningful advance.17 Currently, the 4-drug regimen FOLFIRINOX (folinic acid, fluorouracil [5-FU], oxaliplatin, irinotecan) and the combination of gemcitabine and nab-paclitaxel are standard therapies for metastatic pancreatic cancer, with gemcitabine alone often used for individuals with low performance status. The first approved second line treatment for patients with metastatic PDAC who received gemcitabine in the first line occurred in 2015 and consists of 5-FU + nal-irinotecan.18
The success of gemcitabine- and FOLFIRINOX-based regimens for metastatic disease resulted in their testing and use for adjuvant treatment for earlier stage PDAC.19,20 Still under debate is the relative benefit of chemotherapy or radiation therapy in the preoperative vs postoperative setting and the agents of choice for neoadjuvant therapy for those diagnosed with resectable or borderline resectable disease. Neoadjuvant therapy is used in many U.S. institutions based on reports of clinical trials from Asia21,22 and Europe23 as the results from ongoing U.S. clinical trials are awaited.
Interestingly, there has been an improvement in survival with standard-of-care chemotherapies over time. The median overall survival (OS) with gemcitabine treatment reported in phase 3 trials between 1993 and 2000 was 5.5 months; between 2001 and 2006, 6.2 months; and 2007 and 2012, 8.1 months.17 The combination gemcitabine plus nab-paclitaxel resulted in an 8.5-month median OS in a trial that completed in 201224 and 10.8 months in the control arm of a trial that completed in 2018.25 Presumably this increase reflects experience with the drugs and improvements in supportive care measures.
The success of precision medicine in cancer in general has benefited subsets of patients with pancreatic cancer. Enthusiasm for a precision medicine approach in PDAC was initially dampened by the difficulty and risk in obtaining sufficient tissue and the presence of KRAS mutations in over 90% of cases. However, studies indicated approximately 25% of PDAC tumors contained molecular alterations that suggested potential benefit from investigational or approved therapeutic agents.26-29 The Pancreatic Cancer Action Network’s Know Your Tumor® program, which provides biomarker testing for patients throughout the U.S., reported that individuals with molecular alterations who received targeted therapy had an OS 1 year longer than those who did not receive targeted therapy or with no molecular alteration (2.58 vs 1.51 and 1.32 years median OS, respectively).30 The ‘holy grail’ of PDAC precision medicine would be targeting the common KRAS G12D, G12V, or G12R mutations (41%, 34%, and 16% of PDAC, respectively).31 The recent approval of sotorasib (Lumakras) for KRAS G12C mutant non–small cell lung cancer provides hope that such agents are forthcoming.32
Alterations in BRCA1/2 are currently the most common targetable molecular alteration and are identified in 5% to 10% of PDAC.33 Olaparib (Lynparza), a PARP inhibitor, has been approved in the maintenance setting for patients with PDAC with germline alterations in BRCA1/2 genes.34 Results from the ASCO Targeted Agent and Profiling Utilization Registry (TAPUR) study indicate olaparib efficacy in patients in PDAC with either germline or tumor specific BRCA1/2 inactivating mutations.35 The advent of FDA tissue-agnostic approvals of targeted therapies for biomarker-identified cancers plays an important role in patients with pancreatic cancer realizing the benefits of precision medicine. Although NTRK fusions (<1%)36 and microsatellite instability-high/mismatch repair-deficient alterations (~1%)37 are found only rarely in pancreatic cancer, the existence of these FDA-approved treatment options for these individuals justified NCCN guideline changes to recommend genetic testing for inherited mutations of all patients with pancreatic cancer and biomarker testing of tumor tissue of those with pancreatic cancer seeking treatment.8
PDAC has the reputation of being an immunologically “cold” tumor and non-responsive to single-agent checkpoint inhibitors. The exception is a small subset of molecularly-defined PDAC with microsatellite instability, mismatch repair deficiency, or high tumor mutational burden.38,39 There has been a substantial increase over the past decade in clinical trials testing hypotheses related to the influence of PDAC-associated desmoplasia in excluding T-cells and the presence of abundant immunosuppressive cells.40 Immunotherapy trials now make up 30% of the approximately 150 total PDAC clinical trials open in the U.S. at any one time.41 The complexity of these trials has increased over time; trials in 2011 and 2012 tested a vaccine or an immune modulating agent alone or in combination with gemcitabine; between 2013 and 2015, trials included a checkpoint inhibitor; and the complexity of the immunotherapeutic combinations increased from 2016 onwards. These trends are likely to indicate an acknowledgement of the need to address the immunological complexity of PDAC if we are to hope for a significant benefit for most patients with PDAC.
The Future of Pancreatic Cancer Management
As we contemplate the future, the trajectory for advances in pancreatic cancer management are encouraging. The 5-year survival rate more than doubled over the past 25 years, from 4.6% to 11.2%, whereas survival from all cancers combined exhibited a more modest increase from 62% to 69% (SEER-9, 1990-1992 vs 2011-2017).
Advances for pancreatic cancer are coming at both ends of the spectrum: the detection of earlier stage disease and the management of metastatic disease.The change in guidelines so patients with pancreatic cancer get tested for predisposition genes and inform family members should significantly increase the number of individuals aware of an elevated pancreatic cancer risk. Advances in blood-based biomarkers for early detection will be facilitated by studies collecting pre-diagnostic samples for validation studies, and artificial intelligence approaches to imaging are likely to improve the detection of pancreatic cancer at a much earlier, resectable stage. Improved survival following standard chemotherapies, the growing list of FDA-approved drugs for molecularly defined cancers, and the substantial efforts focused on converting the pancreatic cancer microenvironment into one that is responsive to immunotherapies suggests there will be many more tools in the medical oncologist’s toolkit soon.
The FDA has suggested that master protocol platform trials represent the future of cancer clinical research.42 The pancreatic cancer field has joined this movement, and the Pancreatic Cancer Action Network’s Precision Promisesm, a phase 2/3 registration-ready platform trial for metastatic pancreatic cancer in the first and second line, joins platform trials in several other diseases as a way to streamline and accelerate development and FDA approval of new therapies. We look forward to the day when pancreatic cancer is no longer considered the poster child for a terminal disease.
1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33. doi:10.3322/caac.21654
2. 2021 Snapshot: State of the Oncology Workforce in America. JCO Oncol Pract. 2021;17(5):249. doi:10.1200/OP.21.00166
3. Rahib L, Wehner MR, Matrisian LM, Nead KT. Estimated Projection of US Cancer Incidence and Death to 2040. JAMA Netw Open. 2021;4(4):e214708. doi:10.1001/jamanetworkopen.2021.4708
4. Chari ST, Kelly K, Hollingsworth MA, et al. Early detection of sporadic pancreatic cancer: summative review. Pancreas. 2015;44(5):693-712. doi:10.1097/MPA.0000000000000368
5. Petersen GM. Familial Pancreatic Adenocarcinoma. Hematol Oncol Clin North Am. 2015;29(4):641-53. doi:10.1016/j.hoc.2015.04.007
6. Hu C, Hart SN, Bamlet WR, et al. Prevalence of Pathogenic Mutations in Cancer Predisposition Genes among Pancreatic Cancer Patients. Cancer Epidemiol Biomarkers Prev. 2016;25(1):207-11. doi:10.1158/1055-9965.EPI-15-0455
7. Stoffel EM, McKernin SE, Brand R, et al. Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion. J Clin Oncol. 2019;37(2):153-164. doi:10.1200/JCO.18.01489
8. Tempero MA, Malafa MP, Chiorean EG, et al. Pancreatic Adenocarcinoma, Version 1.2019. J Natl Compr Canc Netw. 2019;17(3):202-210. doi:10.6004/jnccn.2019.0014
9. Maitra A, Sharma A, Brand RE, et al. A prospective study to establish a new-onset diabetes cohort: from the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer. Pancreas. 2018;47(10):1244-1248. doi:10.1097/MPA.0000000000001169
10. Lee LS. Updates in diagnosis and management of pancreatic cysts. World J Gastroenterol. 2021;27(34):5700-5714. doi:10.3748/wjg.v27.i34.5700
11. Goggins M, Overbeek KA, Brand R, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut. 2020;69(1):7-17. doi:10.1136/gutjnl-2019-319352
12. Canto MI, Almario JA, Schulick RD, et al. Risk of neoplastic progression in individuals at high risk for pancreatic cancer undergoing long-term surveillance. Gastroenterology. 2018;155(3):740-751 e2. doi:10.1053/j.gastro.2018.05.035
13. Liu MCO, G.R.; Klein, E.A.; Swanton, C.; Seiden, M.V.; CCGA Consortium. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann Oncol. 2020;31(6):745-759.
14. Springer S, Masica DL, Dal Molin M, et al. A multimodality test to guide the management of patients with a pancreatic cyst. Sci Transl Med. 2019;11(501)doi:10.1126/scitranslmed.aav4772
15. Singhi AD, McGrath K, Brand RE, et al. Preoperative next-generation sequencing of pancreatic cyst fluid is highly accurate in cyst classification and detection of advanced neoplasia. Gut. 2018;67(12):2131-2141. doi:10.1136/gutjnl-2016-313586
16. Farrell JJ, Al-Haddad MA, Jackson SA, Gonda TA. Incremental value of DNA analysis in pancreatic cysts stratified by clinical risk factors. Gastrointest Endosc. 2019;89(4):832-841 e2. doi:10.1016/j.gie.2018.10.049
17. Rahib L, Fleshman JM, Matrisian LM, Berlin JD. Evaluation of pancreatic cancer clinical trials and benchmarks for clinically meaningful future trials: a systematic review. JAMA Oncol. 2016;2(9):1209-16. doi:10.1001/jamaoncol.2016.0585
18. Wang-Gillam A, Li CP, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545-557. doi:10.1016/S0140-6736(15)00986-1
19. Neoptolemos JP, Palmer DH, Ghaneh P, et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017;389(10073):1011-1024. doi:10.1016/S0140-6736(16)32409-6
20. Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018;379(25):2395-2406. doi:10.1056/NEJMoa1809775
21. Motoi F, Kosuge T, Ueno H, et al. Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP05). Jpn J Clin Oncol. 2019;49(2):190-194. doi:10.1093/jjco/hyy190
22. Jang JY, Han Y, Lee H, et al. Oncological Benefits of neoadjuvant chemoradiation with gemcitabine versus upfront surgery in patients with borderline resectable pancreatic cancer: a prospective, randomized, open-label, multicenter phase 2/3 trial. Ann Surg. 2018;268(2):215-222. doi:10.1097/SLA.0000000000002705
23. Versteijne E, Suker M, Groothuis K, et al. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: results of the dutch randomized phase III PREOPANC trial. J Clin Oncol. 2020;38(16):1763-1773. doi:10.1200/JCO.19.02274
24. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691-703. doi:10.1056/NEJMoa1304369
25. Tempero M, Oh DY, Tabernero J, et al. Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: phase III RESOLVE study. Ann Oncol. 2021;doi:10.1016/j.annonc.2021.01.070
26. Waddell N, Pajic M, Patch AM, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518(7540):495-501. doi:10.1038/nature14169
27. Lowery MA, Jordan EJ, Basturk O, et al. Real-time genomic profiling of pancreatic ductal adenocarcinoma: potential actionability and correlation with clinical phenotype. Clin Cancer Res. 2017;23(20):6094-6100. doi:10.1158/1078-0432.CCR-17-0899
28. Cancer Genome Atlas Research Network. Electronic address aadhe, Cancer Genome Atlas Research N. Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell. 2017;32(2):185-203 e13. doi:10.1016/j.ccell.2017.07.007
29. Pishvaian MJ, Bender RJ, Halverson D, et al. Molecular profiling of patients with pancreatic cancer: initial results from the Know Your Tumor Initiative. Clin Cancer Res. 2018;24(20):5018-5027. doi:10.1158/1078-0432.CCR-18-0531
30. Pishvaian MJ, Blais EM, Brody JR, et al. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. Lancet Oncol. 2020;21(4):508-518. doi:10.1016/S1470-2045(20)30074-7
31. Waters AM, Der CJ. KRAS: The critical driver and therapeutic target for pancreatic cancer. Cold Spring Harb Perspect Med. 2018;8(9)doi:10.1101/cshperspect.a031435
32. Skoulidis F, Li BT, Govindan R, et al. Overall survival and exploratory subgroup analyses from the phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated KRAS p.G12C mutated non-small cell lung cancer. J Clin Oncol. 2021;39(15_suppl):9003-9003. doi:10.1200/JCO.2021.39.15_suppl.9003
33. Lai E, Ziranu P, Spanu D, et al. BRCA-mutant pancreatic ductal adenocarcinoma. Br J Cancer. 2021;doi:10.1038/s41416-021-01469-9
34. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317-327. doi:10.1056/NEJMoa1903387
35. Ahn ER. Olaparib (O) in patients (pts) with pancreatic cancer with BRCA1/2 inactivating mutations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study. J Clin Oncol. 2020;38(suppl 15):4637. doi:10.1200/JCO.2020.38.15_suppl.4637
36. Forsythe A, Zhang W, Phillip Strauss U, Fellous M, Korei M, Keating K. A systematic review and meta-analysis of neurotrophic tyrosine receptor kinase gene fusion frequencies in solid tumors. Ther Adv Med Oncol. 2020;12:1758835920975613. doi:10.1177/1758835920975613
37. 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
38. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413. doi:10.1126/science.aan6733
39. Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21(10):1353-1365. doi:10.1016/S1470-2045(20)30445-9
40. Bear AS, Vonderheide RH, O'Hara MH. Challenges and Opportunities for pancreatic cancer immunotherapy. Cancer Cell. 2020;38(6):788-802. doi:10.1016/j.ccell.2020.08.004
41. Matrisian LMM, Rosenzweig A, Moravek C, Duliege AM. Trends in pancreatic cancer clinical trials in the United States. Medical Research Archives. 2021.
42. Woodcock J, LaVange LM. Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med. 2017;377(1):62-70. doi:10.1056/NEJMra1510062