Slicing and Dicing Pancreatic Cancer Into Actionable Nuggets
Authors: Anirban Maitra
Journal: Journal of the National Comprehensive Cancer Network (2017)

Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate of 9%. 1 During the past few years, several large publicly funded initiatives, such as The Cancer Genome Atlas and the International Cancer Genome Consortium, 2 as well as smaller single institution studies, 3,4 have elucidated the comprehensive genomic landscapes of PDAC.These studies have shown that oncogenic KRAS mutations remain the dominant alteration in PDAC, with loss of function mutations of TP53, SMAD4, and CDKN2A rounding off the "big 4" mutations in this disease.Despite the preponderance of these 4 mutational events (each occurs in >50% of tumors), unfortunately none are currently actionable, although considerable preclinical efforts are ongoing for developing antagonists to oncogenic KRAS or the encoded mutant protein.This does not, however, preclude the possibility of other lower-frequency alterations in the PDAC genome that remain eminently actionable.In fact, it has been estimated that as many as 40% of PDAC cases might harbor as many as one actionable alteration based on the current slate of therapeutic agents targeting specific mutations. 5In the accompanying article by Singhi et al (elsewhere in this issue), the authors queried targeted next-generation sequencing (NGS) offered through a commercial fee-forservice provider (Foundation Medicine, Cambridge, MA) in 3,170 PDAC cases and identified 5 PDACs (representing 0.16% of cases) with a somatic alteration in the anaplastic lymphoma kinase (ALK) gene.Remarkably, all 5 cases occurred in patients <50 years of age (by comparison, the median age of onset for PDAC is 65 years), and when specifically stratified by age of onset <50 years, the frequency of ALK gene alterations increased to 1.3%, suggesting preferential occurrence in younger-onset disease.Further parsing of the genomic alterations demonstrated absence of KRAS mutations in all 5 cancers, which is striking, given the near ubiquitous nature of this abnormality in PDAC.Although this raises the specter of a pancreatic metastasis from an ALK-mutant lung primary, radiologic and clinical parameters were most consistent with a PDAC; expectedly, consistent with the generally advanced presentation of PDAC, resected tissue was available in only 1 of 5 cases.Notably, 4 of the 5 patients received one or more small molecule ALK inhibitors approved for ALK-mutant lung cancer (crizotinib, ceritinib, or alectinib), 6 and 3 of them demonstrated at least some degree of objective response, based on imaging or biochemical parameters.There are several pertinent messages one can distill from this study.First, actionable mutations that lead to objective responses can occur in an exceedingly small fraction of cases, such as the 0.16% of somatic ALK mutations observed here.However, it might be possible to enrich for this "zebra" by using simple clinical parameters, such as young age at diagnosis, which pushes the rate of positivity to 1.3%, a prevalence that matches what is observed in lung cancer overall, and justifies the cost-effectiveness of targeted NGS panels for mutation profiling.Second, this approach has a clinical rationale given the ready availability of both first-and second-generation ALK inhibitors, which can be administered once patients have experienced disease progression on current, standard-of-care, first-line cytotoxic chemotherapy regimens.At the same time, one must be cognizant of the fact that, in the current study, we are presented with incomplete data on outcomes, and the rate of sustained response to ALK inhibitors in ALK-mutant PDAC remains unknown.