The prognosis of metastatic pancreatic adenocarcinoma has recently begun to improve. In the last several years, first-line therapy with gemcitabine plus nab-paclitaxel or a regimen of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) has boosted the median overall survival (OS) duration to 8.5 months and 11 months, respectively, in patients with metastatic pancreatic cancer, compared with a historic OS of only 6 months prior to 2011. Moreover, sequencing these two regimens improved median OS to an unprecedented 18 months. Notably, as newer agents become available and undergo testing, there is some indication that certain subgroups of patients may benefit dramatically from therapies targeting specific pathways in pancreatic cancer. There have been several attempts to assess the molecular differences in the driving mechanisms of pancreatic cancers, and to link these to specific therapies that could be remarkably effective in selected patients. These molecular analyses—based primarily on assessment of DNA mutations but also incorporating RNA sequencing and, in some cases, protein expression analysis—are beginning to reveal specific subtypes of pancreatic adenocarcinoma. Identification of the appropriate therapy for these subtypes may lead to further improved OS in the relevant patient populations. In this article, we review seminal articles that have evaluated the molecular architecture of pancreatic cancer. We compare the methods used and the molecular subtypes defined, and assess the predominant subgroups in order to better understand which therapies may improve patient outcomes.
Pancreatic adenocarcinoma is a nearly universally fatal disease and is one of the few cancer types that continues to increase in incidence. In 2016 in the United States, pancreatic cancer was diagnosed in approximately 53,070 patients and caused an estimated 41,780 deaths. Indeed, pancreatic adenocarcinoma, one of the most lethal solid tumors, is expected to become the second leading cause of cancer-related deaths in the United States in the next few years. While the prognosis for patients with metastatic pancreatic adenocarcinoma continues to be very poor, improved outcomes have recently been demonstrated in patients treated with combination chemotherapy. With the availability of new therapies that have undergone clinical testing, it has become clear that agents targeting specific pathways can yield significant clinical benefits in certain subgroups of patients. Thus, there have been several attempts to assess the molecular differences in the driving mechanisms of pancreatic cancers, and to link these differences to specific therapies that could be remarkably effective for selected patients.
Conventional Pathologic Subtyping of Pancreatic Neoplasms
In general, the term “pancreatic cancer” encompasses a mix of pathologies in which the cells originate in the pancreas and are thought to be epithelial in origin; however, the question of the cellular origin of the disease continues to be debated.[3,4] Even with access to modern-day molecular profiling, histology that distinguishes the exact pathologic subtype of pancreatic lesions is still the most clinically informative piece of data (ie, for diagnosis and prognosis). Exocrine pancreatic cancers can have a gland-like appearance (when well differentiated) and are the most common types of pancreatic cancer; the majority are classified as pancreatic ductal adenocarcinoma (commonly referred to as PDAC or PDA). Other forms of exocrine cancers are rare but are typically cystic or can be acinar cell carcinomas. Endocrine cancers are a small subset of all pancreatic cancers (~5%). Pancreatic neuroendocrine tumors are classified as functional (hormone-producing) or nonfunctional (non–hormone-producing).
In Table 1, we have outlined the molecular and histologic features that are traditionally identified in the various pathologic subtypes.[5-9] While histologic features are still used to define and diagnose pancreatic cancer subtypes, more recently, modern molecular techniques such as next-generation DNA sequencing and RNA sequencing have been used to further classify pancreatic cancer subtypes. The hope is to discover better targets and improve the therapeutic options.
Survival Outcomes: Still Based on One-Size-Fits-All Treatment Plans
Despite the dismal prognosis of pancreatic cancer, real progress has been made in terms of improved radiologic response rates and survival duration.[10,11] Studies have also shown a widening of the overall survival (OS) curve, reflecting an increase in the number of patients for whom chemotherapy has provided an exceptional benefit. For example, combination therapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) or with gemcitabine plus nab-paclitaxel yielded much higher response rates than treatment with gemcitabine alone. Moreover, sequencing of these modern regimens improved median OS to 18 months. Further, nearly 20% of patients treated with FOLFIRINOX were alive at 18 months, compared with only 6% treated with gemcitabine alone. Notably, a small subgroup of patients in both trials survived beyond 3 years with metastatic disease.[10,11]
It is interesting to consider that, despite reported median progression-free survival times of only 6.5 months with FOLFIRINOX and 5.5 months with gemcitabine plus nab-paclitaxel, extended survival times were observed. These outcomes suggest that patients who survive with their disease for 18 to 24 months or longer either have exceptionally favorable prognostic factors or have experienced a significant therapeutic benefit that translated into an OS benefit of 1 year or longer after completion of treatment. In fact, given the statistically significant and clinically meaningful differences in the 18-month survival rate among patients treated with FOLFIRINOX or gemcitabine plus nab-paclitaxel rather than gemcitabine alone, the reported survival improvements are likely to be due specifically to characteristics that predict for (and have translated into) an enhanced benefit from chemotherapy. Consequently, there is an opportunity to further enhance patient outcomes by identifying the molecular characteristics of the patients who have shown a better response to each chemotherapy regimen.
It is also evident that the type of targeted therapy used plays a role in the treatment of selected patients with pancreatic cancer, with anecdotal and early-phase reports describing subgroups of patients who have experienced exceptional outcomes. Most notably, patients with genetic defects in the homologous recombination DNA repair pathway (HRD) have experienced significant clinical benefit from poly (ADP-ribose) polymerase (PARP) inhibitor–based and/or platinum-based therapies.[13-16] There is a growing body of evidence that patients treated with regimens that include PARP inhibitors have dramatically higher rates of response and longer survival than patients with typical pancreatic adenocarcinoma that is managed with standard chemotherapy. For example, O’Reilly et al recently presented outcomes for pancreatic cancer patients treated with the combination of gemcitabine, cisplatin, and veliparib. The response rate among patients with confirmed BRCA1 or BRCA2 mutations was 66%, and mean survival time after enrollment was 8.4 months (with several patients alive more than 2 years from the time of diagnosis). The hope in pursuing molecular profiling of pancreatic cancers is to identify additional subgroups of patients with pancreatic cancer who achieve dramatic responses to treatment with targeted therapies—although these subgroups have yet to be defined. Table 2 highlights important studies of molecular subgrouping of pancreatic cancers. Table 3 compares signaling pathways and relevant genes identified in selected studies. Table 4 shows that the identified pancreatic subtypes were generally comparable across several studies, although the study authors sometimes used different labels to define a particular subtype. The Figure is a Venn diagram showing the core signaling pathways that were identified in several seminal pancreatic cancer molecular subtyping studies.
1. American Cancer Society. Cancer facts and figures 2016. http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2.... Accessed February 8, 2016.
2. Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913-21.
3. Kopp JL, Sander M. New insights into the cell lineage of pancreatic ductal adenocarcinoma: evidence for tumor stem cells in premalignant lesions? Gastroenterology. 2014;146:24-6.
4. Kopp JL, von Figura G, Mayes E, et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;22:737-50.
5. Borazanci E, Millis SZ, Korn R, et al. Adenosquamous carcinoma of the pancreas: molecular characterization of 23 patients along with a literature review. World J Gastrointest Oncol. 2015;7:132-40.
6. Wu J, Matthaei H, Maitra A, et al. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med. 2011;3:92ra66.
7. Hackeng WM, Hruban RH, Offerhaus GJ, Brosens LA. Surgical and molecular pathology of pancreatic neoplasms. Diagn Pathol. 2016;11:47.
8. Distler M, Aust D, Weitz J, et al. Precursor lesions for sporadic pancreatic cancer: PanIN, IPMN, and MCN. Biomed Res Int. 2014;2014:474905.
9. Klimstra DS, Pitman MB, Hruban RH. An algorithmic approach to the diagnosis of pancreatic neoplasms. Arch Pathol Lab Med. 2009;133:454-64.
10. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817-25.
11. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691-703.
12. Portal A, Pernot S, Tougeron D, et al. Nab-paclitaxel plus gemcitabine for metastatic pancreatic adenocarcinoma after FOLFIRINOX failure: an AGEO prospective multicentre cohort. Br J Cancer. 2015;113:989-95.
13. Lowery MA, Kelsen DP, Stadler ZK, et al. An emerging entity: pancreatic adenocarcinoma associated with a known BRCA mutation: clinical descriptors, treatment implications, and future directions. Oncologist. 2011;16:1397-402.
14. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33:244-50.
15. Pishvaian MJ, Wang H, Zhuang T, et al. A phase I/II study of ABT-888 in combination with 5-fluorouracil (5-FU) and oxaliplatin (Ox) in patients with metastatic pancreatic cancer (MPC). J Clin Oncol. 2013;31(suppl 4):abstr 147.
16. O’Reilly EM, Lowery MA, Segal MF, et al. Phase IB trial of cisplatin (C), gemcitabine (G), and veliparib (V) in patients with known or potential BRCA or PALB2-mutated pancreas adenocarcinoma (PC). J Clin Oncol. 2014;32(suppl 5s):abstr 4023.
17. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801-6.
18. Collisson EA, Sadanandam A, Olson P, et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med. 2011;17:500-3.
19. Badea L, Herlea V, Dima SO, et al. Combined gene expression analysis of whole-tissue and microdissected pancreatic ductal adenocarcinoma identifies genes specifically overexpressed in tumor epithelia. Hepatogastroenterology. 2008;55:2016-27.
20. Balagurunathan Y, Morse DL, Hostetter G, et al. Gene expression profiling-based identification of cell-surface targets for developing multimeric ligands in pancreatic cancer. Mol Cancer Ther. 2008;7:3071-80.
21. Pei H, Li L, Fridley BL, et al. FKBP51 affects cancer cell response to chemotherapy by negatively regulating Akt. Cancer Cell. 2009;16:259-66.
22. Grutzmann R, Pilarsky C, Ammerpohl O, et al. Gene expression profiling of microdissected pancreatic ductal carcinomas using high-density DNA microarrays. Neoplasia. 2004;6:611-22.
23. Biankin AV, Waddell N, Kassahn KS, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491:399-405.
24. Waddell N, Pajic M, Patch AM, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518:495-501.
25. Moffitt RA, Marayati R, Flate EL, et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet. 2015;47:1168-78.
26. Witkiewicz AK, McMillan EA, Balaji U, et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun. 2015;6:6744.
27. Bailey P, Chang DK, Nones K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531:47-52.
28. 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 Jan 24. [Epub ahead of print]
29. National Comprehensive Cancer Network Guidelines. Pancreatic adenocarcinoma (version 2.2016). https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed February 14, 2017.