Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. In 2016, the American Cancer Society estimated that 53,070 individuals would be diagnosed with PDAC and approximately 41,780 would die of this deadly disease.1 Although surgical resection offers the only possibility of cure, >85% of patients present with inoperable disease at diagnosis. Therefore, chemotherapy is the mainstay of treatment for most patients. Unfortunately, current therapeutic regimens, including gemcitabine plus nab-paclitaxel and FOLFIRINOX (5-fluorouracil, folinic acid, oxaliplatin, and irinotecan), have limited efficacy, with an incremental survival benefit of only a few months in unselected patients. However, significant responses have been observed in small subgroups.2
Whole-exome and whole-genome sequencing studies of large PDAC cohorts have revealed a diverse number of genetic alterations in otherwise histologically similar tumors.3,4 The intertumoral heterogeneity of molecular abnormalities may partly explain the poor response rates to current therapeutic regimens among unselected patients with PDAC.5 Thus, there has been a recent emphasis on a more personalized approach to the treatment of PDAC based on its underlying genetic alterations. For instance, PDACs harboring mutations in DNA repair genes, such as BRCA2 or PALB2, are often sensitive to poly(ADP-ribose) polymerase inhibitors and cisplatin.6 Moreover, mutations in the mismatch repair genes confer susceptibility to immune checkpoint inhibitors.7 However, these “actionable” genetic alterations are relatively uncommon and, consequently, there is an urgent need to identify additional molecular targets.
In recent years, chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene have been the subject of intense clinical investigation.8 The ALK protein is a receptor tyrosine kinase and physiologically expressed within the central nervous system. Translocation of ALK with various partner genes results in an ALK fusion protein and constitutive ALK activation. Several ALK fusion genes have been reported and are considered drivers of tumorigenesis for a wide range of neoplasms. In addition, the ALK protein inhibitors crizotinib, ceritinib, and alectinib have proven efficacy in patients with ALK-rearranged tumors.9,10 Therefore, the ALK fusion protein represents an attractive target for directed therapy, but, to date, has not been reported in PDACs. We examined the prevalence of ALK rearrangements within a large cohort of locally advanced and metastatic PDACs and identified 5 patients with an ALK-rearranged PDAC. We further analyzed their associated clinicopathologic features and molecular profile. Follow-up information was available for 4 patients, including treatment response data with ALK protein inhibitors.
The authors would like to thank Mrs. Robyn L. Roche for outstanding administrative assistance.
Drs. Ali, Chung, Greenbowe, and Ross have employment and stock ownership in Foundation Medicine, Inc. The remaining authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.
This study was supported in part by a grant from the National Pancreas Foundation, Western Pennsylvania Chapter, and the University of Pittsburgh (A.D.S.).
See JNCCN.org for supplemental online content.
American Cancer Society. Key Statistics for Pancreatic Cancer. Available at: http://www.cancer.org/cancer/pancreaticcancer/detailedguide/pancreatic-cancer-key-statistics. Accessed April 4, 2017.
Jones S, Zhang X, Parsons DW et al. . Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008;321:1801–1806.
Samuel N, Hudson TJ. The molecular and cellular heterogeneity of pancreatic ductal adenocarcinoma. Nat Rev Gastroenterol Hepatol 2012;9:77–87.
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;16:1397–1402.
Shaw AT, Yeap BY, Solomon BJ et al. . Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 2011;12:1004–1012.
Friboulet L, Li N, Katayama R et al. . The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov 2014;4:662–673.
Frampton GM, Fichtenholtz A, Otto GA et al. . Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 2013;31:1023–1031.
Lin E, Li L, Guan Y et al. . Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers. Mol Cancer Res 2009;7:1466–1476.
Kelly LM, Barila G, Liu P et al. . Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer. Proc Natl Acad Sci U S A 2014;111:4233–4238.
Soda M, Choi YL, Enomoto M et al. . Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561–566.
Marino-Enriquez A, Ou WB, Weldon CB et al. . ALK rearrangement in sickle cell trait-associated renal medullary carcinoma. Genes Chromosomes Cancer 2011;50:146–153.
Soda M, Takada S, Takeuchi K et al. . A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci U S A 2008;105:19893–19897.
McDermott U, Iafrate AJ, Gray NS et al. . Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer Res 2008;68:3389–3395.
Yoshida A, Tsuta K, Nakamura H et al. . Comprehensive histologic analysis of ALK-rearranged lung carcinomas. Am J Surg Pathol 2011;35:1226–1234.
Gainor JF, Varghese AM, Ou SH et al. . ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res 2013;19:4273–4281.
Graham RP, Oliveira AM, Zhang L. Rare ALK expression but no ALK rearrangement in pancreatic ductal adenocarcinoma and neuroendocrine tumors. Pancreas 2013;42:949–951.
Singhi AD, Ishida H, Ali SZ et al. . A histomorphologic comparison of familial and sporadic pancreatic cancers. Pancreatology 2015;15:387–391.
Katayama R, Lovly CM, Shaw AT. Therapeutic targeting of anaplastic lymphoma kinase in lung cancer: a paradigm for precision cancer medicine. Clin Cancer Res 2015;21:2227–2235.
Doebele RC, Pilling AB, Aisner DL et al. . Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 2012;18:1472–1482.
Varela I, Tarpey P, Raine K et al. . Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 2011;469:539–542.