Dynamic changes during the treatment of pancreatic cancer

This detailed analysis of the clinical descriptions, imaging, pathology, molecular and cellular evolution of the tumors, treatments and responses to chemotherapy, targeted therapies and immunotherapies as well as attempts at the development of personalized medical treatments for a single patient should provide a valuable guide to future directions in cancer treatment.

"They all sacrificed time and effort from other research projects and activities, because they all came to appreciate the rewards of helping an individual patient, perhaps more directly than previous research avenues in a laboratory had permitted."

On December 22, 2011, a patient was diagnosed with an inoperable pancreatic adenocarcinoma. After Folfirinox therapy, the tumor regressed and became operable. It was removed on May 30, 2012. Eighteen months later, metastatic lesions appeared in the lungs and on the rib cage.

It was at this point (Nov.1, 2013) that the family decided to assemble a group of scientists who had interest in and could carry out extensive surveillance of the tumor in the patient and perform experimentation with clinical materials collected from blood and biopsies of the tumor tissue. The purpose of this was to inform and assist the clinicians who were making the decisions about the treatment and care of their patient.

Figure 1: Patient clinical course throughout a four year period. Size of lung and pleural metastatic lesions were used to determine response to therapies (left axis). CA-19-9 levels are plotted, although remain mostly within normal range (right axis).

A time line was created, employing DNA sequencing from blood samples, the production of three dimensional, or organoid, tissue cultures and two-dimensional cell cultures, from serial biopsies in order to follow the changes occurring during treatments and tumor response and progression.

In addition, these experiments addressed a limitation of past DNA sequencing studies with tumor tissue, which explore only one time point in the evolution of a tumor.

This dynamical study follows the changes in DNA sequences and DNA sequence heterogeneity with time and treatment.

The DNA sequences obtained from samples in the blood were compared to those sequence changes found in the organoids made from biopsies taken at different times.

What is clear was that there was a prolonged period of chemotherapy keeping the tumor metastasis under control, and biopsies demonstrate that this gives rise to increasing clonal heterogeneity of the tumor, perhaps resulting in an EMT with epigenetic changes and altered gene expression.

The tumor in vivo evolves under therapeutic selections and there is a need for greater monitoring and speed in understanding this evolution, so that the therapeutic choices keep up with the tumor evolution and heterogeneity.

Full text - https://doi.org/10.18632/oncotarget.24483

Correspondence to - Arnold J. Levine - alevine@ias.edu

Keywords - pancreatic cancer, genomic instability, organoids, epithelial-mesenchymal transition