It is well-known that patients with pancreatic body/tail cancer usually have a poorer prognosis than those with pancreatic head cancer probably due to more advanced pathologic stages at initial diagnosis[1]. To better understand the prognostic relevance and distinct tumor biology, we should compare the two subtypes of PDACs in comparable conditions such as AJCC TNM stages and pathology grade. A large cohort analysis using the National Cancer Database of the United States from 1998 to 2011 demonstrated that among 40,980 cases of resected PDAC, pancreatic head cancers had advanced tumor stage, higher nodal positivity, worse tumor grade and poorer overall survival than pancreatic body/tail cancers[2]. A recent strictly propensity score-matched (e.g., race, gender, marital status, TMN stage and pathology grade) study including 4,571 resected T1 stage PDACs from Surveillance, Epidemiology, and End Results (SEER) database (2004–2014) provided the best evidence showing the prognostic value of tumor location in early-stage PDACs up to now[8]. They found that patients with pancreatic head cancer had a worse prognosis compared to those with pancreatic body/tail cancers. Body/tail location was further proved to be an independent indicator for better chances of survival in T1 PDAC patients. In this sense, pancreatic body/tail cancer seems to be a less malignant phenotype as compared to pancreatic head cancer.
However, the genomic and transcriptomic profiling comparison between pancreatic head and body/tail cancers using resected PDAC samples provided the opposite results. Both Birnaum’s[4] and Dreyer’s[5] studies showed pancreatic body/tail cancers were associated with ‘squamous phenotype’[9] and presented more aggressive tumor biology such as epithelial-to-mesenchymal transition (EMT), inflammation and metabolic reprogramming. This study displayed a 2-fold higher SMAD4 mutation rate in pancreatic body/tail cancers than pancreatic head cancers among early-stage tumors (I-II). Inactivating mutation in SMAD4 does not initiate the tumor genes in PDAC but serve as secondary genetic alterations following KRAS mutation[10]. Interestingly, SMAD4/TGF-beta signaling is involved in squamous/EMT transition in PDAC[11]. Therefore, our results supported the previous two studies that pancreatic body/tail cancers might be more ‘squamous phenotype’ than pancreatic head cancers. We also assume that the molecular diversity between pancreatic head and body/tail cancers starts from the clonal expansion phase[10] but not the tumor initiation.
When PDAC developed to the late stages (III-IV), there was a remarkable difference in cancer genome between the two subtypes. We found significantly higher KRAS mutations (e.g., substitution, indels, and gene amplification), more enriched mutation frequencies in MAPK pathway and a lower rate of druggable genomic alterations in pancreatic body/tail cancers than pancreatic head cancers. Activating mutation of KRAS is almost ubiquitous (~ 95%) in PDAC and is an essential event in both tumor initiation and progression[12]. Mutant KRAS drives PDAC development and promotes tumor cell proliferation via altered metabolic pathways including stimulation of glucose uptake and utilization, reprogrammed glutamine metabolism and increased autophagy[12]. Furthermore, KRAS driver mutations lead to the activation of Wnt and MAPK pathways, which controls tumor cell proliferation, motility, metabolism and survival[13]. The results were consistent with a large cohort study including 9,952 patients with metastasized PDAC from the Netherlands Cancer Registry (2005–2015), which demonstrated that pancreatic tail cancers had more metastatic sites and worse survival[14]. It seems that pancreatic body/tail cancers are more biological aggressive than pancreatic head cancers as PDAC has progressed to late stage.
Besides, the genomic variant results indicated that the choice of therapy strategies could refer to tumor location as well as mutated genes. Birnbaum et al[4] suggested checkpoint inhibitors as neoadjuvant treatment for pancreatic head cancers and anti-EGFR targeted therapies for pancreatic body/tail cancers. This study displayed a significantly lower rate of KRAS wild type in pancreatic body/tail cancers than pancreatic head cancers, indicating a low efficiency of Regorafenib, Panitumumab, and Cetuximab, which is FDA approved drugs for the treatment of colorectal cancer patients with KRAS wild type. A novel small-molecular inhibitor AMG510 targeting to a KRAS mutation G12C presented valid anti-cancer ability for patients with non-small cell lung cancer in the phase I clinical trial [15] and may be of help for the 100% KRAS mutated late-stage pancreatic body/tail cancers. Anti-EGFR or BRAF targeted therapies were not recommended in either pancreatic head or body/tail cancers because of the extremely low druggable mutation frequencies.
There were strengths as well as limitations in this study. This was the first study including both early and late stages PDACs and comparing the genomic profiles between pancreatic head and body/tail cancers. Thus, it is a more comprehensive comparison than the previous studies. But the sample size was rather small. Moreover, this study used ultra-deep panel sequencing to detect extremely low frequencies. But the panel was limited to 450 genes and the previously defined molecular subtypes [16] could not be analyzed.