Refining the Treatment of Pancreatic Cancer From Big Data to Improved Individual Survival

Abstract

Pancreatic cancer is one of the most lethal cancers world-wide most notably in Europe and North America. Great strides have been made in combining the most effective conventional therapies to improve survival at least in the short and medium term. The start of treatment can only be made once a diagnosis is made, which at this point the tumor volume is already very high in the primary cancer and systemically. If caught at the earliest opportunity (in circa 20% patients) surgical resection of the primary followed by combination chemotherapy can achieve 5-year overall survival rates of 30–50%. A delay in detection of even a few months after symptom onset will result in the tumor having only borderline resectabilty (in 20–30% of patients), in which case the best survival is achieved by using short course chemotherapy before tumor resection as well as adjuvant chemotherapy. Once metastases become visible (in 40–60% of patients) cure is not possible, palliative cytotoxics only being able to prolong life by few months. Even in apparently successful therapy in resected and borderline resectable patients the recurrence rate is very high. Considerable efforts to understand the nature of pancreatic cancer through large scale genomics, transcriptomics and digital profiling, combined with functional preclinical models, using genetically engineered mouse models and patient derived organoids, have identified the critical role of the tumor microenvironment in determining the nature of chemo- and immuno-resistance. This functional understanding has powered fresh and exciting approaches for the treatment of this cancer.

Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC

“…These cells survive initial drug treatments by an epigenetic and/or transcriptional adaption that allows a drug-tolerant, slow-cycling ‘persister’ state to emerge. Clinically, this persister state resembles minimal residual disease from which relapse can occur if treatment is discontinued or if persister cells acquire a drug-resistant driver alteration due to continued drug therapy 48 .…”

Neoadjuvant treatment of pancreatic ductal adenocarcinoma: Whom, when and how

“…Nevertheless, several elements of neoadjuvant therapy for PDAC, such as the most effective treatment plan, the incorporation of radiotherapy, and the identification of suitable candidates for neoadjuvant therapy, still require further clarification. Since other tumors with a much better prognosis have a greater number of average mutations, such as breast and colorectal cancers, and because the genetic spectra of colorectal, brain, and pancreatic tumors are similar, the average number of genetic alterations in PDAC tumors is insufficient to explain the abnormally poor prognosis and response to therapy[ 57 , 58 ].…”

Personalized treatment in localized pancreatic cancer

“…The development of cytotoxic therapies for different stages of pancreatic cancer has primarily relied on empirical approaches. Reductionist attempts to develop treatments by targeting key pathogenic gene alterations have seen limited success, with most targets having a prevalence ranging from 0.1% to 5%, and the survival advantage provided by these agents being only a few months, despite the frequency of altered mutational pathways [94,95]. The Know Your Tumor Registry represents the largest pancreatic cancer targeted therapy program.…”

“…Emerging findings from our research laboratory indicate that intrinsic drug-tolerant cells, often referred to as "persisters," have the capacity to arise from a preexisting subset of cancerous cells subsequent to neoadjuvant chemotherapy (Fig. 4; [95,[101][102][103]). These persister-like cells adapt to the impact of chemotherapy by enhancing the expression of genes such as CYP3A5 and other co-expressed drug-metabolizing genes.…”