Evolutionary Origins of Recurrent Pancreatic Cancer

Abstract

Surgery is the only curative option for Stage I/II pancreatic cancer, nonetheless most patients will recur after surgery and die of their disease. To identify novel opportunities for management of recurrent pancreatic cancer we performed whole exome or targeted sequencing of 10 resected primary cancers and matched intrapancreatic recurrences or distant metastases. We identified that adjuvant or first-line platinum therapy corresponds to an increased mutational burden of recurrent disease. Recurrent disease is enriched for mutations that activate Mapk/Erk and PI3K/AKT signaling and develops from a monophyletic or polyphyletic origin. Treatment induced genetic bottlenecks lead to a modified genetic landscape and subclonal heterogeneity for driver gene alterations in part due to intermetastatic seeding. In one patient what was believed to be recurrent disease was an independent (second) primary tumor. These findings advocate for combination therapies with immunotherapy and routine post-treatment sampling as a component of management of recurrent pancreatic cancer.

Longitudinal profiling of circulating tumour DNA for tracking tumour dynamics in pancreatic cancer

“…Evidence of longitudinal clonal evolution was further observed in this patient, with the expansion of new subclonal structures in ctDNA following adjuvant gemcitabine treatment. These results indicate that longitudinal monitoring of ctDNA mutation profiles may have value for informing on changes in the molecular landscape of resectable PDAC tumours following surgery and adjuvant chemotherapy treatment, as indicated in recent studies (47).…”

Activated regulatory T-cells, dysfunctional and senescent T-cells dominate the microenvironment of pancreatic cancer

“…The spatial analysis of cell distribution in the tumour has revealed a unique localisation of Tregs to the stroma (Figure 4d). These observations, in light of a recent study in a murine model of PDAC that showed depletion of Tregs to result in disease worsening through an increase in pathogenic fibroblasts [44], highlight the need to understand the details of Treg/fibroblast interactions and its role in disease progression. A possible strategy proposed from this work would be to block exclusively the activity of the ICOS + TIGIT + Tregs population while forgoing any depletion approaches that might result in severe adverse effects.…”

Pancreatic cancer pathology viewed in the light of evolution

“…The mutations that arise in patients with recurrent and metastatic PDAC after other therapies are only beginning to be characterized [72]. Some of these mutations arise in genes rarely if ever mutated in primary untreated pancreatic cancers.…”

“…Not surprisingly, these mutations are typically were present in pre-existing clones and provide additional oncogenic advantage or help to overcome environmental pressures such as targeted therapies. Examples of such mutated genes include genes coding for members of the MEK-ERK pathway and for the PI3K-MTOR pathway [72]. Finally, heterogeneity of mutated driver genes can exist within different metastatic clones, indicating that different tumor microenvironments can drive the selection of distinct subclones which may result in different adaptations to targeted therapies in different metastatic sites [72].…”