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.
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